Comprehensive Metabolic Profiling Reveals a Lipid-Rich Fingerprint of Free Thyroxine Far Beyond Classic Parameters.

Objective: Thyroid hormones are ubiquitously involved in human metabolism. However, the precise molecular patterns associated with alterations in thyroid hormones levels remain to be explored in detail. A number of recent studies took great advantage of metabolomics profiling to outline the metabolic actions of thyroid hormones in humans. Methods: Among 952 participants in the Study of Health in Pomerania, data on serum free thyroxine (FT4) and thyrotropin and comprehensive nontargeted metabolomics data from plasma and urine samples were available. Linear regression analyses were performed to assess the association between FT4 or thyrotropin and metabolite levels. Results and Conclusion: After accounting for major confounders, 106 of 613 plasma metabolites were significantly associated with FT4. The associations in urine were minor (12 of 587). Most of the plasma metabolites consisted of lipid species, and subsequent analysis of highly resolved lipoprotein subclasses measured by proton nuclear magnetic resonance spectroscopy revealed a consistent decrease in several of these species (e.g., phospholipids) and large low-density lipoprotein and small high-density lipoprotein particles. The latter was unique to men. Several polyunsaturated and saturated fatty acids displayed an association with FT4 in women only. A random forest-based variable selection approach using phenotypic characteristics revealed higher alcohol intake in men and an adverse thyroid state and menopause in women as the putative mediating factors. In general, our observations have confirmed the lipolytic and lipogenic effect of thyroid hormones even in the physiological range and revealed different phenotypic characteristics (e.g., lifestyle differences) as possible confounders for sex-specific findings.

Age- and gender-specific reference intervals of TSH and free T4 in an iodine-replete area: Data from Korean National Health and Nutrition Examination Survey IV (2013-2015).

BACKGROUND: Establishment of the reference interval of thyroid-stimulating hormone (TSH) is critical in the diagnosis of thyroid dysfunction and is affected by age, gender, iodine nutrition, and ethnicity. The aim of this study was to determine the reference intervals of TSH and free thyroxin (FT4) from a large, nationwide data of Korea where iodine intake is more than adequate. METHODS: We analyzed data from the Korea National Health and Nutrition Examination Survey VI that measured serum TSH, FT4, and thyroid peroxidase antibody from 7,061 individuals (urinary iodine measurement in 6,565). Age- and gender-specific reference intervals were established from 95% confidence limits from the 2.5 to 97.5 percentile of TSH (log-transformed) and FT4 in reference populations. RESULTS: The geometric mean of TSH was 2.16 ± 0.01 mIU/L, with the lowest value found in the middle aged group (2.04 ± 0.02 mIU/L) and higher values noted in age groups of 10-19 and over 70 years (2.38 ± 0.02 and 2.32 ± 0.07 mIU/L, respectively). The association of TSH and age was U-shaped. The overall reference interval of TSH was 0.59-7.03 mIU/L. Mean FT4 was 1.25 ± 0.003 ng/dL (16.09 ± 0.039 pmol/L), and it showed a small but continuous decrease after 20 years of age (P < 0.001). There was a significant positive correlation between TSH and urine iodine concentration (r = 0.154, P < 0.001). CONCLUSIONS: The reference interval of TSH in Korea, where iodine intake is above the requirement, was 0.59-7.03 mIU/L and showed U-shaped change with age, which was a similar pattern to iodine intake. The reference interval of FT4 was 0.92-1.60 ng/dL. The geometric mean and upper limit of TSH were higher than those of Western populations, reflecting the paramount importance of iodine intake on thyroid function.

Triclosan and triclocarban exposure and thyroid function during pregnancy-A randomized intervention.

Triclosan and triclocarban (TCs) are broad-spectrum microbicides found in household and personal wash products. We sought to determine whether TC exposure from wash products or urinary triclosan level modified thyroid function during pregnancy or anthropometric measurements at birth. A randomized intervention of wash products with or without TCs, including toothpaste, enrolled pregnant women from 20 weeks' gestation. Urinary triclosan, TSH, T4 and T3 were assessed at enrollment, 36weeks' gestation and/or post-delivery; anthropometric measures at birth were ascertained from medical records. 78 and 76 mothers were assigned to the TC-containing and no-TC-containing product arms, respectively. No differences were observed in any thyroid function measure at any time point or in any anthropometric measurement at birth between either exposure arms or lowest and highest urinary triclosan quartile groups. TCs from wash products, primarily liquid and bar soaps, did not affect thyroid function measures during pregnancy or babies' anthropometric measures at delivery.

Correlation between urinary cadmium and thyroid hormones in outdoor workers exposed to urban stressors.

OBJECTIVES: The aim of this study is to evaluate whether exposure to low concentrations of cadmium (Cd) can have effects on the thyroid hormone level of outdoor workers exposed to urban pollutants. METHODS: The study was conducted on a final sample of 277 individuals (184 males and 93 females). The environmental monitoring of Cd was evaluated through the use of portable dosimeters, while the biological monitoring was achieved through the assessment of urinary Cd and thyroid hormones. The total sample was divided according to sex and task. The Pearson's correlation coefficient among the variables was calculated after subdivision on the basis of sex and task. The multiple linear regression was performed to take into account the major confounding factors. RESULTS: Statistical tests showed a negative correlation between urinary Cd levels and free triiodothyronine and free thyroxine and a positive correlation between urinary Cd and thyroid-stimulating hormone levels. CONCLUSIONS: Our early results seem to point out that occupational exposure to low concentrations of Cd present in urban air affects the thyroid hormone levels in exposed workers.

Urinary thyroid hormone parameters test for evaluating the thyroid function during pregnancy.

It is necessary to regularly monitor thyroid function status during pregnancy. The repeated tests on serum thyroid hormones are invasive and can be uncomfortable. Sampling urine may provide an effective alternative. The primary aim of this study was to investigate if there is a correlation between the serum and urine levels of thyroid hormones during pregnancy. The secondary aim was to investigate their variation during pregnancy. This study collected the serum specimens of 30 healthy pregnant women at 9-12, 14-17, 23-26, and 37-40 weeks of gestation, respectively, simultaneously along with random urine specimens. This study compared the median levels of free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) in serum and urine among four gestational stages. The differences were statistically significant (p < 0.05). There were positive correlations between serum FT3 (sFT3) and uFT3/uRBP (the ratio of urine FT3(uFT3) and urine retinol binding protein (uRBP)), r = 0.38 (I(2) = 0%, 95% CI: 0.21 ∼ 0.54), serum FT4 (sFT4) and uFT4/uRBP (the ratio of urine FT4 (uFT4) and uRBP), r = 0.29 (I(2) = 68.9%, 95% CI: 0.07 ∼ 0.51), and no correlation between serum TSH (sTSH) and uTSH/uRBP (the ratio of urine TSH (uTSH) and uRBP), r = 0.11 (I(2) = 86.7%, 95% CI: -0.24 ∼ 0.45). In conclusion, the levels of sFT3, sFT4, uFT3/uRBP, and uFT4/uRBP continued to decrease until the 27th week of gestation, when it was almost invariant. The levels of uFT3/uRBP and uFT4/uRBP correlated well with the sFT3 and sFT4 during pregnancy, which may provide a more convenient and secure way to monitor the maternal thyroid function status during pregnancy.

Stir bar sorptive extraction combined with high performance liquid chromatography-ultraviolet/inductively coupled plasma mass spectrometry for analysis of thyroxine in urine samples.

tIn this work, polyethyleneglycol (PEG)/hydroxyl polydimethylsiloxane (OH-PDMS)/γ -mercaptopropyltrimethoxysilane (γ -MPTS) coated stir bar was prepared by sol­gel process and its extraction performance for the extraction of amphoteric thyroxines (3,3',5,5'-tetraiodothyronin, T(4); 3,3',5-triiodothyronine, T(3); reversed-3,3',5-triiodothyronine, rT(3)) and their metabolite (3,5-diiodothyronine,T2) was studied. The preparation reproducibility of PEG/OH-PDMS/γ -MPTS coated stir bar was investigated, and the relative standard deviations (RSDs) in the same batch and among different batches were 3.3­14.3% (n = 5) and 7.7­16.6% (n = 3), respectively. The prepared PEG/OH-PDMS/γ -MPTS coated stir bar could be reused for more than 20 times. Based on this fact, a novel method of stir bar sorptive extraction (SBSE) combined with high performance liquid chromatography (HPLC)-ultraviolet (UV)and HPLC-inductively coupled plasma mass spectrometry (ICP-MS) for the analysis of target thyroxinesin human urine samples was developed. The influencing factors of SBSE, such as sample pH, extraction time, stirring rate, salt effect, desorption solution and desorption time, were studied in detail, and the analytical performance of the proposed method was evaluated under the optimized conditions. The enrichment factors (EFs) of the developed method for four target thyroxines were in the range of 14.9­70.4(theoretical enrichment factor was 100). The RSDs were ranging from 4.0% to 13.8% for SBSE-HPLC-UV (c = 25 µg/L, n = 6) and from 3.7% to 6.1% for SBSE-HPLC-ICP-MS (c = 0.5 µg/L, n = 5). The linear range obtained by SBSE-HPLC-UV was 2­500 µg/L for T(2)and 5­500 µg/L for rT3, T(3)and T(4), with correlation coefficients (r) ranging from 0.9957 to 0.9998, respectively, while the linear range obtained by SBSE-HPLC-ICP-MS was 0.05­500 µg/L for T(2) and rT(3), 0.10­200 µg/L for T(3) and 0.05­200 µg/L for T(4)with r ranging from 0.9979 to 0.9998, respectively. The limits of detection (LODs) for the target thyroxines were 0.60­2.20 µg/L for SBSE-HPLC-UV and 0.0071­0.0355 µg/L SBSE-HPLC-ICP-MS, respectively. The developed method was applied for the determination of target thyroxines in urine samples, and the recovery for the spiking samples obtained by SBSE-HPLC-UV was in the range of 81.6­137.6% for human urine,while the recovery for the spiking urine samples obtained by SBSE-HPLC-ICP-MS were in the range of 72.0­121.5%.

Maternal and neonatal urinary iodine status and its effect on neonatal TSH levels in a mildly iodine-deficient area.

OBJECTIVE: Iodine deficiency and excess are the most important factors that affect screening and recall rates of congenital hypothyroidism. The purpose of this study was to investigate the urinary iodine status in newborns and their mothers and its effects on neonatal thyroid-stimulating hormone (TSH) levels in a mildly iodine-deficient area. METHODS: A total of 116 newborns and their mothers were included in the study. Urinary iodine levels were measured from healthy mothers and their babies on the 5th day following birth. Neonatal TSH levels were screened, and TSH and free thyroxine (fT4) levels were measured on the 15th day in the recall cases. T4 treatment was started in infants with high TSH and low fT4 levels. These measurements were repeated on the 30th day in these newborns. RESULTS: Ninety-nine percent of the mothers included in the study were using iodized salt. The median urinary iodine level in the newborns was 279 µg/L, while it was 84 µg/L in their mothers. The rate of iodine deficiency among the mothers was 56.8%, and the rate of iodine excess was 8.6%. This rate was 10.3% for iodine deficiency and 61.2% for iodine excess in the newborns. The recall rate at the screening was 9.5% (n=11). The urinary iodine levels were above 200 µg/L in three newborns who had transient hyperthyrotropinemia. CONCLUSIONS: Iodine deficiency was more frequently observed in nursing mothers, and iodine excess was more frequently seen in their newborns. The iodine excess noted in the newborns was attributed to the use of antiseptics containing iodine. The iodine excess leads to increases in recall rates, screening costs, and frequency of transient hyperthyrotropinemia.

Environmental perchlorate and thiocyanate exposures and infant serum thyroid function.

BACKGROUND: Breastfed infants rely on maternal iodine for thyroid hormone production required for neurodevelopment. Dietary iodine among women of childbearing age in the United States may be insufficient. Perchlorate (competitive inhibitor of the sodium/iodide symporter [NIS]) exposure is ubiquitous. Thiocyanate, from cigarettes and diet, is a weaker NIS inhibitor. Environmental perchlorate and thiocyanate exposures could decrease breast milk iodine by competitively inhibiting NIS in lactating breasts (thus impairing infants' iodine availability), and/or infants' thyroidal NIS to directly decrease infant thyroid function. The current study assessed the relationships between environmental perchlorate and thiocyanate exposures and infant serum thyroid function. METHODS: Iodine, perchlorate, and thiocyanate in breast milk, maternal and infant urine, and infant serum thyroid function tests were cross-sectionally measured in Boston-area women and their 1-3 month-old breastfed infants. Univariate and multivariable analyses assessed relationships between iodine, perchlorate, thiocyanate, thyroid-stimulating hormone (TSH), and free thyroxine (FT4) levels. RESULTS: In 64 mothers and infants, median (range) iodine levels were 45.6 µg/L (4.3-1080) in breast milk, 101.9 µg/L (27-570) in maternal urine, and 197.5 µg/L (40-785) in infant urine. Median perchlorate concentrations were 4.4 µg/L (0.5-29.5) in breast milk, 3.1 µg/L (0.2-22.4) in maternal urine, and 4.7 µg/L (0.3-25.3) in infant urine. There were no correlations between infant TSH or FT4 and iodine, perchlorate, and thiocyanate levels in breast milk, maternal urine, and infant urine. In multivariable analyses, perchlorate and thiocyanate levels in breast milk, maternal urine, and infant urine were not significant predictors of infant TSH or FT4. CONCLUSIONS: Boston-area mothers and their breastfed infants are generally iodine sufficient. Although environmental perchlorate and thiocyanate are ubiquitous, these results do not support the concern that maternal and infant environmental perchlorate and thiocyanate exposures affect infant thyroid function.

Triple bioaffinity mass spectrometry concept for thyroid transporter ligands.

For the analysis of thyroid transporter ligands, a triple bioaffinity mass spectrometry (BioMS) concept was developed, with the aim at three different analytical objectives: rapid screening of any ligand, confirmation of known ligands in accordance with legislative requirements, and identification of emerging yet unknown ligands. These three purposes share the same biorecognition element, recombinant thyroid transport protein transthyretin (rTTR), and dedicated modes of liquid chromatography-mass spectrometry (LC-MS). For screening, a rapid and radiolabel-free competitive inhibition MS binding assay was developed with fast ultrahigh performance-liquid chromatography-electrospray ionization-triple-quadrupole-MS (UPLC-QqQ-MS) as the readout system. It uses the nonradioactive stable isotopic thyroid hormone (13)C(6)-L-thyroxine as the label of which the binding to rTTR is inhibited by any ligand such as thyroid drugs and thyroid endocrine disrupting chemicals (EDCs). To this end, rTTR is either used in solution or immobilized on paramagnetic microbeads. The concentration-dependent inhibition of the label by the natural thyroid hormone l-thyroxine (T4), as a model analyte, is demonstrated in water at part-per-trillion and in urine at part-per-billion level. For confirmation of identity of known ligands, rTTR was used for bioaffinity purification for confirmation of naturally present free T4 in urine. As a demonstrator for identification of unknown ligands, the same rTTR was used again but in combination with nano-UPLC-quadrupole time-of-flight-MS (nLC-Q-TOF-MS) and urine samples spiked with the model "unknown" EDCs triclosan and tetrabromobisphenol-A. This study highlights the potential of BioMS using one affinity system, both for rapid screening and for confirmation and identification of known and unknown emerging thyroid EDCs.

Tyrosine kinase inhibitors noncompetitively inhibit MCT8-mediated iodothyronine transport.

CONTEXT: Tyrosine kinase inhibitors (TKI) are used for the treatment of various cancers. Case reports and clinical trials have reported abnormal thyroid function tests (TFT) after treatment with sunitinib, imatinib, sorafenib, dasatinib, and nilotinib. An increased requirement for levothyroxine was reported in thyroidectomized patients during TKI treatment. OBJECTIVE: We hypothesized that abnormal TFT are compatible with inhibition of thyroid hormone (TH) transporters and subsequently reduced pituitary-TH feedback. Monocarboxylate transporter 8 (MCT8) is a TH transmembrane transporter in brain, pituitary, and other organs. MCT8 mutation leads to abnormal TFT in patients and respective mouse models. We tested whether TKI are able to inhibit MCT8-mediated TH uptake into cells. DESIGN: Madin-Darby-canine kidney (MDCK1) cells stably expressing human MCT8 were exposed in vitro to TKI at increasing concentrations, and MCT8-mediated [(125)I]T(3) uptake and efflux were measured. The mode of inhibition was determined. RESULTS: TKI exposure dose-dependently inhibited MCT8-dependent T(3) and T(4) uptake. IC(50) values for sunitinib, imatinib, dasatinib, and bosutinib ranged from 13-38 µm, i.e. similar to the Michaelis-Menten constant K(m) for T(3) and T(4), 4 and 8 µm, respectively. Kinetic experiments revealed a noncompetitive mode of inhibition for all TKI tested. CONCLUSIONS: Partial inhibition by TKI of pituitary or hypothalamic TH feedback may increase TSH or increase the levothyroxine requirement of thyroidectomized patients. It is still possible that other mechanisms contribute to TKI-mediated impairments of TFT, e.g. altered metabolism of TH. Bosutinib was not previously reported to alter TFT.

Maternal thyroid function in different conditions of iodine nutrition in pregnant women exposed to mild-moderate iodine deficiency: an observational study.

OBJECTIVE: We examined the effect of different conditions of nutritional iodine intake on maternal thyroid function throughout gestation in a cohort of healthy, anti-thyroid antibody-negative women from a mild-moderately iodine-deficient (ID) area. DESIGN: Observational cohort study. PATIENTS: The study included 168 women receiving prenatal preparations containing 150 µg of iodine from early pregnancy (150-I group); 105 women who had regularly used (>2 years) iodized salt prior to becoming pregnant (I-salt group); 160 women neither taking iodine supplements nor using iodized salt (no-I group). MEASUREMENTS: Maternal TSH, FT3 and FT4 were determined throughout gestation. RESULTS: Mean TSH concentrations were higher among the 150-I women than in the remaining two groups, and in a high proportion of them, TSH values were found to exceed the upper limit for gestational age. Conversely, the prevalence of low free-thyroxine levels in the 150-I women was similar to that observed in the I-salt women and markedly lower than that recorded for the no-I group. CONCLUSIONS: The regular use of iodine-containing supplements proved effective in reducing the risk of inappropriately low FT4 levels during pregnancy. The observed TSH increase in 150-I women may be because of a transient stunning effect on the thyroid gland, occurring as a result of the abrupt increase in daily iodine intake. Whilst the importance of gestational iodine supplementation is undisputed, we believe that in mild-moderately ID areas, women considering conception should be advised to take iodine supplementation for several months prior to pregnancy.

Contributors to secondary osteoporosis and metabolic bone diseases in patients presenting with a clinical fracture.

BACKGROUND: Previously undetected contributors to secondary osteoporosis and metabolic bone diseases (SECOB) are frequently found in patients with osteoporosis, but the prevalence in patients at the time they present with a clinical fracture is unknown. METHODS: All consecutive patients with a recent clinical vertebral or nonvertebral fracture, who were able and willing to be investigated (n = 626: 482 women, 144 men, age range 50-97 yr) had bone mineral density and laboratory investigations (serum calcium, inorganic phosphate, 25-hydroxyvitamin D, creatinine, intact PTH, TSH, free T(4), serum and urine protein electrophoresis, and in men also serum testosterone). RESULTS: Known SECOB contributors were present in 23.0% of patients and newly diagnosed SECOB contributors in 26.5%: monoclonal proteinemia (14 of 626), renal insufficiency grade III or greater (54 of 626), primary (17 of 626) and secondary (64 of 626) hyperparathyroidism, hyperthyroidism (39 of 626), and hypogonadism in men (12 of 144). Newly diagnosed SECOBs, serum 25-hydroxyvitamin D less than 50 nmol/liter (in 63.9%), and dietary calcium intake less than 1200 mg/d (in 90.6%) were found at any age, in both sexes, after any fracture (except SECOB in men with finger and toe fractures) and at any level of bone mineral density. CONCLUSION: At presentation with a fracture, 26.5% of patients have previously unknown contributors to SECOB, which are treatable or need follow-up, and more than 90% of patients have an inadequate vitamin D status and/or calcium intake. Systematic screening of patients with a recent fracture identifies those in whom potentially reversible contributors to SECOB and calcium and vitamin D deficiency are present.

[No thyroxin dose seemed sufficient--why?]. / Miksi mikään tyroksiiniannos ei tuntunut riittävän?

The health status of a woman with type 1 diabetes was followed during pregnancy in a maternity hospital. In addition to insulin, thyroxine therapy was applied due to hypothyreosis as a consequence of Basedow disease. Nephropathy and significant proteinuria had developed as complications of diabetes, with the proteinuria increasing considerably during pregnancy. Simultaneously thyroxine doses increased to exceptionally high levels. The cause of increasing doses was found to be secretion of thyroxine into urine. The phenomenon has been described earlier, but it is not generally recognized.

Exacerbation of underlying hypothyroidism caused by proteinuria and induction of urinary thyroxine loss: case report and subsequent investigation.

OBJECTIVE: To describe a patient with excess urinary thyroxine (T4) excretion and worsening of preexisting hypothyroidism in the setting of nephrotic syndrome and to determine whether excess urinary T4 excretion is present in other patients with proteinuria. METHODS: We present data regarding the patient's initial presentation, diagnostic studies, and course of her illness. We suspected urinary T4 loss to be the cause of her presentation and analyzed her urine sample for total T4. We also analyzed differences in urinary T4 excretion in 22 patients with proteinuria and 16 control patients without proteinuria. Relevant medical literature is reviewed. RESULTS: A 44-year-old woman presented with a 3-month history of increasing fluid retention, weight gain, and fatigue. She had long-standing hypothyroidism on a stable levothyroxine dosage, 125 mcg/d. She had gained 27 kg and had developed significant edema. She had a grossly elevated thyroid-stimulating hormone level of 91 mIU/L. Her condition worsened, and a urinary protein measurement was 14.06 g/24 h-diagnostic of nephrotic syndrome. The levothyroxine dosage was increased to 225 mcg/d. Urinary total T4 concentration in a 24-hour sample was 59.0 microg/L (83.1 microg/24 h), indicating that a substantial fraction of her orally ingested T4 was lost in urine. Urinary total T4 excretion was significantly higher in patients with proteinuria (mean +/- standard deviation, 18.0 +/- 18.2 microg/L) vs control patients without proteinuria (mean, 3.8 +/- 1.8 microg/L) (P = .0014). CONCLUSION: In the patient described, urinary T4 loss due to proteinuria and nephrotic syndrome resulted in a severe exacerbation of underlying hypothyroidism.

Lycopus europaeus (Gypsywort): effects on the thyroidal parameters and symptoms associated with thyroid function.

The aim of the prospective two-armed open study was to examine the effect of Lycopi europaei herba on thyroid function and on associated symptoms during a 3-month follow-up phase. The study population consisted of patients with a basal TSH<1.0 mU/l and hyperthyroidism-associated symptoms. For the first time, the T3/T4 excretion in 24h urine was measured as a primary objective parameter. As secondary parameters, further hormones, the general condition and the symptoms associated with hyperthyroidism were registered. The urinary T4 excretion was significantly increased in Lycopus europaeus-treated patients (p=0.032). It is supposed that renal mechanisms cause the increased T4 excretion either by a modification within the glomeruli or by impaired reabsorption. Symptoms being specific to the thyroid gland were diminished, as e.g. the increased heart rate in the morning. The Lycopus europaeus preparation showed a good tolerance. These findings confirm positive effects of Lycopus europaeus in slight forms of hyperthyroidism.

[Determining the thyroid hormones T3 and T4 in the urine: an unreliable test for hypothyroidism]. / Bepaling van schildklierhormoon (T3 en T4) in de urine: een weinig betrouwbare test voor de diagnose 'hypothyreoïdie'.

A 24-year-old woman complained of tiredness, sensitivity to cold, and feelings of depression. A diagnosis of hypothyroidism based on decreased 24 h urinary T3 and T4 excretion was made, and she was treated with levothyroxin. No blood tests were done. She was referred with the question if she had other endocrine disorders. Her periods were regular, and on physical examination no abnormalities except slight acne were found. Similarly, hypothyroidism was diagnosed by decreased thyroid hormone excretion in 24 h urine, again without blood tests, in a 68-year-old woman whose mother had a goitre, and who had already been prescribed liothyronine. She had no complaints, and physical examination was unremarkable. The thyroid gland was not palpable. Thyroid peroxidase antibodies were absent in both patients. After discontinuation of medication with thyroid hormones they both remained euthyroid. It is concluded that thyroid disease did not exist in those 2 patients. Measurement of 24 h urinary T3 and T4 excretion is not an accurate diagnostic test for hypothyroidism.