Thyroxine-binding Globulin Concentrations Research Articles

A-059 Evaluation of Free Thyroxin Levels in Patients with Low Thyroxin Binding Globulin Concentrations: Is There Interference in the FT4 Indirect Method?

Abstract Background Thyroxine-binding globulin (TBG) is the major carrier of thyroid hormones in serum. Variations in the serum concentration of TBG determine proportional variations in the total serum concentrations of T4 and T3, without implying changes in function, as long as the free fraction remains normal. Several common clinical conditions lead to significant alterations in TBG levels, the most important factor behind low levels being genetic defects. As TBG is encoded by a gene located on the X chromosome, the defects are more easily manifested in males. Differences in FT4 concentrations were observed in sera from subjects with TBG abnormalities, when FT4 are measured by different immunoassays, specially at extremes of TBG concentrations. The objective of this study was to evaluate FT4 levels by indirect method in patients with low TBG concentrations. Methods We analyzed blood samples requesting serum TBG, TSH and FT4 levels from patients admitted to a private reference clinical laboratory in Brazil, from January 01, 2017 to December 31, 2022. Anonymized data on laboratory tests was available from a database of the local Laboratory Information System. All the patients included had TSH within the reference range, 0.4–4.3 mUI/mL (ECLIA, Modular, Roche). FT4 was measured by ECLIA (0.7–1.8 ng/dL) and TBG by ICMA, Immulite, Siemens, 13–39 mcg/mL. Results 357 patients with low TBG levels were evaluated, 220 (62%) men, 137 (38%) women; mean age 35 yrs (19 d to 88 yrs). They were divided in six groups according TBG levels (mcg/mL): <3.5–17 (M 15, F2); 3.5 to 6.0 - 26 (M 20, F 6); 6.1 to 8.0 - 30 (M 25, F 5); 8.1 to 9.9 - 59 ( M 32, F 27); 10.0 to 11.9 - 139 (M 78, F 61); 12.0 to 12.9 - 86 (M 50, F 36). Three patients had FT4 levels above 1.8 (1.85; 1.87 and 1.96) ng/mL, all them male, with TBG levels <3.5; 5.79 and 9.53 ng/mL, respectively. Conclusion FT4 Indirect methods are developed taking into account the presence, in the serum, of a thyroxine binding capacity within the normal range, a fact that does not occur in individuals with extreme TBG deficiency. In this study, we found only one slightly elevated FT4 value among 17 patients with TBG values below 3.5 mcg/mL, suggesting little interference of very low TBG levels in this indirect free T4 method.

Binding Characteristics of Thyroid Hormone Distributor Proteins to Thyroid Hormone Metabolites.

Background: In contrast to the thyroid hormones (THs) 3,3',5-triiodothyronine (T3) and 3,3',5,5'-tetraiodothyronine (thyroxine or T4), the binding characteristics of the thyroid hormone distributor proteins (THDP), thyroxine-binding globulin (TBG), albumin, and transthyretin in relation to TH metabolites are mostly lacking. In this study, we determined the distribution and binding affinity of TH metabolites to THDP, which is important for adequate interpretation of TH metabolite concentrations. Methods: Distribution of 125I-3,3'-diiodothyronine (3,3'-T2), -T3, -3,3',5'-triiodothyronine (rT3), -3,3',5-triiodothyroacetic acid (TA3), and -3,3',5,5'-tetraiodothyroacetic acid (TA4) to TBG, transthyretin, and albumin was determined by agar gel electrophoresis. The rank order of affinity (IC50) of TBG and transthyretin to thyronine (T0), 3-monoiodothyronine (3-T1), 3,5-diiodothyronine (3,5-T2), 3,3'-T2, T3, rT3, T4, TA3, and TA4 was determined with a radioligand, competitive binding assay. In healthy subjects, associations of serum TBG, transthyretin, and albumin with TH and its metabolites were analyzed using multiple linear regression models, adjusted for sex and age. Results: While T3 and T4 are predominantly bound to TBG, we demonstrated that the predominant THDP of 3,3'-T2 and rT3 is albumin, of TA3 is transthyretin and albumin, and of TA4 is transthyretin. With the radioligand binding assay, we showed that the rank order of affinity was T4>TA4 = rT3>T3>TA3 = 3,3'-T2 > 3-T1 = 3,5-T2>T0 for TBG (IC50-range: 0.36 nM to >100 μM) and TA4>T4 = TA3>rT3>T3 > 3,3'-T2 > 3-T1 > 3,5-T2>T0 for transthyretin (IC50-range: 0.94 nM to >100 μM). TBG, transthyretin, and albumin were not associated with T0, 3-T1, 3,3'-T2, rT3, and TA4. Conclusions: Differences in serum TBG, transthyretin, and albumin concentrations within the reference interval do not influence serum concentrations of T0, 3-T1, 3,3'-T2, rT3, and TA4. Distribution of TH metabolites between THDP differs from T4 and T3, which predominantly bind to TBG. The results from our study have potential clinical importance for adequate interpretation of TH metabolism in (patho)physiology.

Persisting neuroendocrine abnormalities and their association with physical impairment 5\xa0years after critical illness

BackgroundCritical illness is hallmarked by neuroendocrine alterations throughout ICU stay. We investigated whether the neuroendocrine axes recover after ICU discharge and whether any residual abnormalities associate with physical functional impairments assessed 5 years after critical illness.MethodsIn this preplanned secondary analysis of the EPaNIC randomized controlled trial, we compared serum concentrations of hormones and binding proteins of the thyroid axis, the somatotropic axis and the adrenal axis in 436 adult patients who participated in the prospective 5-year clinical follow-up and who provided a blood sample with those in 50 demographically matched controls. We investigated independent associations between any long-term hormonal abnormalities and physical functional impairments (handgrip strength, 6-min walk distance, and physical health-related quality-of-life) with use of multivariable linear regression analyses.ResultsAt 5-year follow-up, patients and controls had comparable serum concentrations of thyroid-stimulating hormone, thyroxine (T4), triiodothyronine (T3) and thyroxine-binding globulin, whereas patients had higher reverse T3 (rT3, p = 0.0002) and lower T3/rT3 (p = 0.0012) than controls. Patients had comparable concentrations of growth hormone, insulin-like growth factor-I (IGF-I) and IGF-binding protein 1 (IGFBP1), but higher IGFBP3 (p = 0.030) than controls. Total and free cortisol, cortisol-binding globulin and albumin concentrations were comparable for patients and controls. A lower T3/rT3 was independently associated with lower handgrip strength and shorter 6-min walk distance (p ≤ 0.036), and a higher IGFBP3 was independently associated with higher handgrip strength (p = 0.031).ConclusionsFive years after ICU admission, most hormones and binding proteins of the thyroid, somatotropic and adrenal axes had recovered. The residual long-term abnormality within the thyroid axis was identified as risk factor for long-term physical impairment, whereas that within the somatotropic axis may be a compensatory protective response. Whether targeting of the residual abnormality in the thyroid axis may improve long-term physical outcome of the patients remains to be investigated.Trial registration ClinicalTrials.gov: NCT00512122, registered on July 31, 2007 (https://www.clinicaltrials.gov/ct2/show/NCT00512122).Graphical

Thyroxine-binding globulin, peripheral deiodinase activity, and thyroid autoantibody status in association of phthalates and phenolic compounds with thyroid hormones in adult population

Exposure to consumer chemicals such as phthalates and phenolic compounds has been associated with thyroid hormone disruption in humans. However, information related to factors that may influence such associations, e.g., transport and activation of the hormones, and autoimmunity status, is limited. In the present study, we employed a subpopulation of adults (n = 1,254) who participated in the Korean National Environmental Health Survey (KoNEHS) 2015–2017, and associated urinary concentrations of major phthalate metabolites, bisphenol A (BPA), and parabens, with thyroid hormone-related measures, including free and total T3 and T4, TSH, thyroxine-binding globulin (TBG), calculated peripheral deiodinase (DIO) activity, and thyroid autoantibodies of thyroperoxidase (TPO) and thyroglobulin (Tg). Phthalate metabolites were negatively associated with total T4 and free T3, and positively associated with total T3. These observations could be explained by TBG levels and calculated peripheral DIO activity that were positively associated with phthalates exposure. In contrast, BPA was positively associated with total T4 and negatively associated with total T3, without any changes in TBG concentration. Serum TPO and Tg antibodies were not associated with urinary phthalate metabolites and BPA. However, thyroid autoantibody status appeared to modulate the association of some phthalates with thyroid hormones. For parabens, little to negligible association was observed. The results of our observation show potential underlying mechanisms of phthalates-induced thyroid hormone disruption, and suggests the importance of consideration of thyroid autoimmunity status in association studies for thyroid disrupting chemicals.

Familial dysalbuminemic hyperthyroxinemia confounding management of coexistent autoimmune thyroid disease.

SummaryFamilial dysalbuminemic hyperthyroxinemia (FDH) is a cause of discordant thyroid function tests (TFTs), due to interference in free T4 assays, caused by the mutant albumin. The coexistence of thyroid disease and FDH can further complicate diagnosis and potentially result in inappropriate management. We describe a case of both Hashimoto’s thyroiditis and Graves’ disease occurring on a background of FDH. A 42-year-old lady with longstanding autoimmune hypothyroidism was treated with thyroxine but in varying dosage, because TFTs, showing high Free T4 (FT4) and normal TSH levels, were discordant. Discontinuation of thyroxine led to marked TSH rise but with normal FT4 levels. She then developed Graves’ disease and thyroid ophthalmopathy, with markedly elevated FT4 (62.7 pmol/L), suppressed TSH (<0.03 mU/L) and positive anti-TSH receptor antibody levels. However, propylthiouracil treatment even in low dosage (100 mg daily) resulted in profound hypothyroidism (TSH: 138 mU/L; FT4: 4.8 pmol/L), prompting its discontinuation and recommencement of thyroxine. The presence of discordant thyroid hormone measurements from two different methods suggested analytical interference. Elevated circulating total T4 (TT4), (227 nmol/L; NR: 69–141) but normal thyroxine binding globulin (TBG) (19.2 µg/mL; NR: 14.0–31.0) levels, together with increased binding of patient’s serum to radiolabelled T4, suggested FDH, and ALB sequencing confirmed a causal albumin variant (R218H). This case highlights difficulty ascertaining true thyroid status in patients with autoimmune thyroid disease and coexisting FDH. Early recognition of FDH as a cause for discordant TFTs may improve patient management.Learning points:The typical biochemical features of familial dysalbuminemic hyperthyroxinemia (FDH) are (genuinely) raised total and (spuriously) raised free T4 concentrations due to enhanced binding of the mutant albumin to thyroid hormones, with normal TBG and TSH concentrations.Given the high prevalence of autoimmune thyroid disease, it is not surprising that assay interference from coexisting FDH may lead to discordant thyroid function tests confounding diagnosis and resulting in inappropriate therapy.Discrepant thyroid hormone measurements using two different immunoassay methods should alert to the possibility of laboratory analytical interference. The diagnosis of FDH is suspected if there is a similar abnormal familial pattern of TFTs and increased binding of radiolabelled 125I-T4 to the patient’s serum, and can be confirmed by ALB gene sequencing.When autoimmune thyroid disease coexists with FDH, TSH levels are the most reliable biochemical marker of thyroid status. Measurement of FT4 using equilibrium dialysis or ultrafiltration are more reliable but less readily available.

Maternal Euthyroid Hyperthyroxinemia May Reduce Preterm Birth Rate in Multiparous Women

Hypothyroidism, defined as thyrotropin (TSH) above and free thyroxine (fT4) serum level below the reference rage, as well as hyperthyroidism, defined as suppressed TSH and elevated thyroid hormones exceeding the upper limit of the reference range, may have major impacts on fertility and pregnancy outcome. Ideally, euthyroidism, defined as TSH and fT4 in the reference range, should be established and preserved during pregnancy prior to gestation. High estrogen levels during pregnancy stimulate the synthesis of maternal thyroxine-binding-globulin (TBG) in the liver, increasing TBG serum concentration by 2 - 3 fold compared to the initial value and affecting thus maternal fT4 serum level. As a consequence, maternal thyroid function adapts by increasing synthesis and secretion of thyroxine. TBG-induced elevation of serum thyroxine either total or free in the absence of hyperthyroidism is defined as euthyroid hyperthyroxinemia. Since TBG concentration declines first after delivery, pregnancy-induced euthyroid hyperthyroxinemia constitutes a physiological metabolic state. Depending on functional capacity, maternal thyroid may exhaust, resulting in hypothyroxinemia, which increases the risk of fetal neurodevelopmental impairment and preterm birth. The study aims to determine whether L-Thyroxine (L-T4) replacement, sustaining pregnancy-induced maternal euthyroid hyperthyroxinemia during the whole pregnancy by keeping fT4 level in the high normal reference range might reduce preterm birth rate. Preterm birth rate of women with singleton gestation and L-T4-induced high normal fT4 level constituting the study group (n = 918) was compared with the preterm birth rate of women with singleton gestation (n = 6414) who completed a questionnaire concerning L-T4 administration during pregnancy. Two groups were formed. In group A we compared the preterm birth rate between women with L-T4-induced high normal fT4 level and a control group without L-T4 administration during pregnancy. In group B we compared the preterm birth rate of women already receiving L-T4 prior to conception, maintaining dosage to keep fT4 level in the high normal reference range during gestation to a control group with L-T4 intake during pregnancy. The preterm birth rates in group A declined by 51% (p = 0.01) and in group B by 87% (p = 0.001) in multiparous women, while in primiparous the preterm birth rate was similar between study and the control group. Sustaining a high normal fT4 level during pregnancy with L-T4 may significantly reduce preterm birth rate in multiparous women.

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.

Persistent Organic Pollutants and Transthyretin-Bound Thyroxin in Plasma of Inuit Women of Childbearing Age

The Inuit population of Nunavik (Northern Quebec, Canada) is highly exposed to persistent organic pollutants (POPs) through their traditional diet. Some POPs, i.e., hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs), pentachlorophenol (PCP), and perfluorooctane sulfonate (PFOS), compete with thyroxin (T4) for binding sites on transthyretin (TTR), a T4 transport protein found in plasma and cerebrospinal fluid. We tested the hypothesis that these TTR-binding compounds decrease circulating concentrations of T4 bound to TTR (T4-TTR) in Inuit women of reproductive age. We measured the concentration of T4-TTR in plasma samples obtained from 120 Inuit women (18-39 years old) by combining native-polyacrylamide gel electrophoresis and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. Total T4, TTR, and thyroxin-binding globulin (TBG) concentrations were also determined, while POPs levels had been previously measured. The mean T4-TTR concentration was 8.4 nmol/L (SD = 2.4) with values ranging from 2.9 to 14.4 nmol/L. Linear regression analysis revealed that TTR, TBG, and total T4 concentrations were significant predictors (p < 0.002) of T4-TTR levels (total adjusted R-squared = 0.26, p < 0.0001) but not levels of OH-PCBs, chlorophenols, or PFOS. Our results suggest that circulating levels of these TTR-binding compounds in Inuit women of childbearing age are not high enough to affect TTR-mediated thyroid hormone transport. The possibility of increased delivery of these compounds to the developing brain requires further investigation.

Permanent and transient congenital hypothyroidism in full-term and preterm born infants

Congenital hypothyroidism (CH) is one of the most common endocrine disorders in the infant population. It is also one of the most important causes of foreseeable brain damage and severe mental impairment. Current views on CH pathogenesis, screening schema and treatment standards have been presented. Also outlined have been the newest reports on the impact on CH epidemiology and classification generated by the introduction of low TSH cut-off (6 mU/l).The use of low TSH cut-off allowed the detection of an unsuspected number of children with neonatal hypothyroidism, evolving in mild permanent thyroid dysfunction later in life. Constantly growing, especially in developed countries, number of preterm infants is a separate group of children, mainly with transient fluctuations in thyroid function. Thyroid gland function develops and matures during fetal life, with production of serum thyroxine (T4) beginning around 12 weeks gestation and increasing to term. Infants born prior to term have lower cord serum T4 concentrations which correlate with gestational age or/and birth weight. This is partially a result of lower thyroxine-binding globulin (TBG) concentrations. The cord serum free thyroxine (FT4) concentrations also correlate with gestational age, but they are not proportionately as low as cord T4 concentration. Preterm infants have a postnatal thyrotropin (TSH) surge and rise in serum T4 and triiodothyronine (T3), which is qualitatively similar to, but quantitatively smaller than term infants. In contrast to term infants, preterm infants often experience a fall in serum T4 and T3 in the first week of life to below birth levels. This drop appears to be the result of many factors, including nutritional problems and decreased hepatic TBG production, immaturity of hypothalamic-pituitary control of the thyroid gland, immaturity of the thyroid gland itself, and increased tissue utilization of T4. Several studies have correlated different measures of morbidity and mortality in the preterm infant with lower serum T4 concentrations. This has led to speculation that T4 treatment might be beneficial in improving these complications of prematurity, in particular the neurological outcome. Latest studies do not confirm that hypothyroidism in preterm infants is for them harmless. Many factors, however, influence mental development of those children. Thus, treatment strategies, including thyroid hormone substitution, should consider both the etiology of the hypothyroidism and the impact of aforementioned factors. There is no “hard evidence” to support introducing thyroid hormone supplementation in preterm infants as a rule.

Measurement of Total Rather Than Free Thyroxine in Pregnancy: The Diagnostic Implications

In light of several recent recommendations to use total thyroxine (T4) measurements in the diagnosis of thyroid function in pregnancy (in particular, "Clinical Practice Guidelines for Hypothyroidism in Adults," cosponsored by the American Thyroid Association and the American Association of Clinical Endocrinologists, which promote the use of T4 over free T4 [FT4 ]), we have examined the implications of employing T4 for diagnostic discrimination in both pregnant and nonpregnant patient panels. Use of T4 assays has significant drawbacks in this regard, and we believe that the suggestion is a retrograde step in thyroid function testing. Analysis of the interplay between the concentrations of T4 and thyroxine-binding globulin (TBG), typifying their respective reference ranges in either the nonpregnant or pregnant euthyroid state, shows that the effective T4 range is widened significantly by the accompanying hidden variation in TBG levels. Accordingly FT4 assays that fully compensate for serum T4-binding protein concentrations should discriminate dysfunctionality from normality more efficiently than total hormone measurements, whether in pregnant or nonpregnant states. The euthyroid FT4 reference ranges typical of late pregnancy should also be more compact than those for the total hormone, because of the increased dominance of higher, though equivalently variable TBG concentrations on T4 levels. Parallel effects on T4 from similarly variable, though lower concentrations of TBG are indicated in the nonpregnant group. While acknowledging the difficulties in FT4 measurement arising from inconsistent calibration of present-day commercial assays, this finding questions the recommendation that total hormone assays should supersede the former in pregnancy.

Serum levels of hydroxylated PCBs, PCBs and thyroid hormone measures of Japanese pregnant women

The purpose of this study was to investigate the associations between serum concentrations of hydroxylated PCBs (OH-PCBs) and PCBs and measures of thyroid hormone status of Japanese pregnant women. The concentrations of free thyroxine (fT4), thyroid stimulating hormone (TSH), and thyroxine binding globulin (TBG) as well as 16 OH-PCB isomers and 29 PCB isomers were analyzed in the serum of 129 women sampled in the first trimester of gestation. Dietary and lifestyle information of the subjects was obtained by self-administered questionnaire. Multiple regression analysis was performed using measures of thyroid hormones as the dependent variable and serum levels of OH-PCBs/PCBs, urinary iodine concentration, and other potential covariates (age, BMI, smoking, etc.) as independent variables. Geometric mean (GM) concentration of the sum of 16 isomers of OH-PCBs was 120pg/g wet wt. and that of 29 isomers of PCBs was 68ng/g lipid wt., respectively, in the serum of the subjects. Iodine nutrition was considered adequate to high from urinary iodine level (GM, 370μg/g creatinine). The mean concentration of TSH, fT4 and TBG was 1.34±1.37μIU/mL, 1.22±0.16ng/dL and 33.0±6.4μg/mL, respectively, with a small number of subjects who were outside the reference range. Multiple regression analysis revealed that serum concentrations of OH-PCBs/PCBs were not significantly associated with any of the measures of thyroid hormone status. Exposure/body burden of OH-PCBs and PCBs at environmental levels does not have a measurable effect on thyroid hormones.

Management of thyroid diseases in pregnancy

Thyroxine binding globulin (TBG) level increases during pregnancy due to the effects of oestrogen1. The increased TBG concentrations lead to elevation of the total thyroxine (T4) and triiodothyronine (T3) but not the free thyroxine (FT4) and free triiodothyronine (FT3) concentrations. This phenomenon is called euthyroid hyperthyroxinaemia and should be considered in interpreting the thyroid functions in pregnant women.

Medications that distort in vitro tests of thyroid function, with particular reference to estimates of serum free thyroxine

The combination of serum thyroid-stimulating hormone (TSH) with measurement of circulating thyroid hormones greatly improves sensitivity and specificity of thyroid diagnosis, but these assays are not impeccable. Estimation of serum free T4 conveniently accommodates variations in the concentration of thyroxine-binding globulin (TBG), but no current technique reliably reflects the in vivo free T4 concentration in numerous other situations. The effect of circulating competitors that increase T4 and T3 in vivo, in particular, many medications, is under-estimated by current free hormone estimates that involve sample dilution. Non-esterified fatty acids generated during sample storage and incubation can spuriously increase the measured free T4 estimate, especially after in vivo treatment with heparin. These artefacts are unlikely to be overcome by current assay strategies. Total serum T4, corrected for alterations in TBG concentration, gives a more robust estimate of thyroxine concentration than current methods of free hormone estimation and should now be reintroduced as the 'gold standard'.

Sex steroids and the thyroid

Thyroid function is modulated by genetic and environmental causes as well as other illnesses and medications such as gonadal or sex steroids. The latter class of drugs (sex steroids) modulates thyroid function. Gonadal steroids exert their influence on thyroid function primarily by altering the clearance of thyroxine-binding globulin (TBG). While oestrogen administration causes an increase in serum TBG concentration, androgen therapy results in a decrease in this binding protein. These effects of gonadal steroids on TBG clearance and concentration are modulated by the chemical structure of the steroid being used, its dose and the route of administration. Despite the gonadal steroids-induced changes in serum TBG concentrations, subjects with normal thyroid glands maintain clinical and biochemical euthyroidism without changes in their serum free thyroxine (T4) or thyroid-stimulating hormone (TSH) levels. In contrast, the administration of gonadal steroids to patients with thyroid diseases causes significant biochemical and clinical alterations requiring changes in the doses of thyroid medications. Similarly, gonadal steroid therapy might unmask thyroid illness in previously undiagnosed subjects. It would be prudent to assess thyroid function in subjects with thyroid disease 6-8 weeks after gonadal steroid administration or withdrawal.

Inherited thyroxine-binding globulin excess. Study in a kindred.

A three-generation family with hereditary high thyroxine-binding globulin (TBG) serum levels has been studied. All patients were clinically euthyroid and did not have a goiter. Four females of the eleven members of the kindred had elevated TBG (range: 34-56 micrograms/ml), total thyroxine (T4) and total triiodothyronine (T3) levels, but normal free T4 (fT4) and normal response of thyroid stimulating hormone (TSH) to intravenous application of thyrotropin-releasing hormone (TRH). Microheterogeneity of TBG studied by isoelectric focusing showed a normal pattern. No variations of the four main bands as seen in other causes of TBG excess like liver diseases, estrogen therapy or pregnancy could be measured. The changes in TBG concentration seem to be due to an abnormal gene expression controlling synthesis of TBG.

Thyroid Function and Plasma Concentrations of Polyhalogenated Compounds in Inuit Adults

BackgroundSeveral ubiquitous polyhalogenated compounds (PHCs) have been shown to alter thyroid function in animal and in vitro studies. So far, epidemiologic studies have focused on the potential effect of a small number of them, namely, polychlorinated biphenyls (PCBs) and some organochlorines (OCs), without paying attention to other important PHCs.ObjectivesWe investigated the relationship between exposure to several PHCs and thyroid hormone homeostasis in Inuit adults from Nunavik.MethodsWe measured thyroid parameters [thyroid-stimulating-hormone (TSH), free thyroxine (fT4), total triiodothyronine (tT3), and thyroxine-binding globulin (TBG)] and concentrations of 41 contaminants, including PCBs and their metabolites, organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), perfluorooctanesulfonate (PFOS), and a measure of dioxin-like compounds, detected in plasma samples from Inuit adults (n = 623).ResultsWe found negative associations between tT3 concentrations and levels of 14 PCBs, 7 hydroxylated PCBs (HO-PCBs), all methylsulfonyl metabolites of PCBs (MeSO2-PCBs), and 2 OCPs. Moreover, we found negative associations between fT4 levels and hexachlorobenzene Concentrations. TBG concentrations were inversely related to 8 PCBs, 5 HO-PCBs, and 3 OCPs. Exposure to BDE-47 was positively related to tT 3, whereas PFOS concentrations were negatively associated with TSH, tT3, and TBG and positively with fT4 concentrations.ConclusionExposure to several PHCs was associated with modifications of the thyroid parameters in adult Inuit, mainly by reducing tT3 and TBG circulating concentrations. The effects of PFOS and BDE-47 on thyroid homeostasis require further investigation because other human populations display similar or higher concentrations of these chemicals.

Point: Legitimate and Illegitimate Tests of Free-Analyte Assay Function

In the history of clinical immunoassay, even up to the present day, no group of tests has been subjected to more scrutiny and controversy than analog-type free-analyte assays (1)(2)(3)(4). Unfortunately, inappropriate design of many experiments has led users to an incorrect perspective of how analog assays work. An analysis of the important series of studies by Nelson and coworkers (5)(6)(7)(8)(9)(10) shows that most experiments were conducted outside the valid working limits of analog-type or 2-step free-analyte assays. Here we explore the legitimacy of this viewpoint. In gold-standard methods of equilibrium dialysis and ultrafiltration, free analyte is first separated from that bound to serum proteins. Only then is the free analyte measured by what essentially is a high-sensitivity total analyte assay. For these methods, testing of assay parameters such as recovery of added analyte, linearity of response, and cross-reactivity are legitimate, applying equally to total analyte measurements. When the antibody probe is in direct contact with serum, however, the situation is radically different. For bound thyroxine (T4), serum contains a low-concentration, high-affinity binding protein (thyroxine-binding globulin) and high-concentration, low-affinity proteins (transthyretin and albumin). Free and total analyte are nonlinearly related (except with zero-thyroxine-binding globulin serum) (11). Recovery and linearity experiments in such conditions are thus not feasible, becoming increasingly less accurate at higher thyroxine-binding globulin concentrations (11). Analog-type and equilibrium dialysis/ultrafiltration methods must be calibrated differently. With gold-standard assays, direct calibration is done gravimetrically with known quantities of analyte, a method that is not possible with analog assays. Analog-type methods are calibrated by secondarily applying the values originally obtained from gold-standard methods to the …

Influence of carbamazepine on serum thyroxine and triiodothyronine in patients with epilepsy.

Hypothyroidism induced by anti-epileptic drug treatment gave rise to thyroid function test studies in patients treated with carbamazepine (CBZ) only. In 42 patients on long-term CBZ treatment thyroxine (T4), free T4-index (FT4I), and triiodothyronine (T3) concentrations in serum were significantly lower than in controls, while triiodothyronine uptake (T3U) and thyrotropin (TSH) concentrations did not differ between patients and controls. In 12 patients starting on CBZ, means T4, calculated FT4 and thyroxine binding globulin (TBG) were 1-5 months later reduced compared to the initial levels. Thus, CBZ reduced thyroid hormones, TBG and FT4I. A CBZ-induced increase in conversion and metabolism of the thyroid hormones could explain this effect. The normal T3U values and decreased concentrations of TBG make a competitive CBZ binding to TBG less probable. Although the thyroid hormones levels were found lowered in the patients, all remained clinically euthyroid during the study.

Effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on thyroid hormones and androgen parameters: conventional vs. extended-cycle use

BackgroundThis study was conducted to investigate the effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on thyroid hormones and androgen parameters. Study designThyroid and androgen parameters were measured in 59 women treated with a monophasic combined oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest (EE/DNG) either conventionally (13 cycles with 21 days of treatment+7 days without hormones) or according to an extended-cycle regimen (four extended cycles with 84 days of continuous administration of EE/DNG, followed by a hormone-free interval of 7 days). Blood samples were taken on Days 21–26 of the preceding control cycle and on Days 19–21 of the 3rd and 13th conventional cycle, or on Days 82–84 of the first and fourth extended cycle. ResultsAt both time points, the serum concentrations of thyroxine-binding globulin were elevated by about 65% in both treatment regimens. Likewise, both groups showed an increase in total triiodothyronine (T3) and total thyroxine (T4) by 30–40%, and no change in free T4. Until the 12th month of conventional treatment, the level of free T3 remained unchanged but decreased slightly during the extended-cycle regimen. In both groups there was a rise of sex hormone-binding globulin by 210–230% after 3 months and by 220–250% after 12 months. The levels of total testosterone were reduced by about 40% and those of free testosterone by 55–65% after 3 and 12 months. ConclusionThe results suggest that, during conventional and extended-cycle treatment with EE/DNG, a steady state in the effects on thyroid hormones and androgen parameters was reached within 3 months and that the changes in the various hormonal parameters did not substantially differ between conventional and extended-cycle regimen.

Congenital Hypothyroidism Following Maternal Exposure throughout Pregnancy to Imatinib.

Imatinib mesylate has revolutionized treatment of Chronic Myeloid Leukemia. Yet for women of child bearing age problems may arise during pregnancy. While continuation of the drug is in the interest of maternal health, the safety of this approach for the fetus has been questioned. Therapy is therefore usually immediately interrupted on recognition of pregnancy. Only three successful pregnancies have been reported to date in which imatinib was continued. A 34-year-old woman of Chinese descent in complete cytogenetic and major molecular remission (i.e. 3-log reduction of BCR-ABL transcripts) of her CML in chronic phase on 400mg imatinib daily continued treatment during conception and throughout pregnancy. After an uneventful full term pregnancy she gave birth to an apparently healthy son. The mother retained her major molecular remission. Routine screening for congenital hypothyroidism of her child however repeatedly revealed an elevated TSH, rising from 11 mU/l at the age of 1 week to15 mU/l at 4 weeks, associated with a relatively low free T4 of 24.8 and 17.4 pmol/l respectively. Thyroglobulin and thyroxine binding globulin concentrations were normal for age. The mother was euthyroid and had no detectable anti-thyroid antibodies. A mild primary hypothyroidism was suspected. An ultrasound showed no developmental defect of his thyroid gland and a 123I scan with a perchlorate discharge test ruled out an intra-thyroidal iodide organification defect. There was no family history of congenital hypothyroidism. The child was put on levothyroxine and is currently doing well. Hypothyroidism has been noticed as a potential side effect of imatinib therapy in thyroidectomized patients receiving levothyroxine and has been ascribed to enhanced non-deiodination clearance of T4 (de Groot et al Clin Pharmacol Ther 2005; 78:433–8). An induction of uridine diphosphate-glucuronosyl transferases by imatinib was hypothesized as mechanism for an altered levothyroxine metabolism in these patients. Congenital hypothyroidism has to the best of our knowledge not been reported as a potential consequence of imatinib therapy.