Serum Thyroxine-binding Globulin Research Articles

Partial Thyroid Hormone-Binding Globulin Deficiency: A Case Report and Literature Review.

Thyroxine binding globulin (TBG) deficiency is a rare thyroid disease, mostly caused by genetic mutations and acquired by X-linked recessive inheritance. The clinical features of children with TBG deficiency and their family members were summarised and the Serpina7 gene mutation was analysed, providing a reference for the differentiation of TBG deficiency. Thyroid function was detected in TBG deficient patients, and genetic analysis was performed using polymerase chain reaction (PCR) and direct DNA sequencing to detect the characteristics of TBG mutants. Using "thyroxine binding globulin, gene and mutation" as keywords, PubMed (biomedical literature database), Web of Science and other databases were searched for relevant studies to collect and summarise relevant information. The TBG (14.7 μg/mL), 70% triiodothyronine (T3) (<0.3 nmol/L), total T3 (Tr3) (<0.05 ng/mL) and thyroxine (T4) (14.72 nmol/L) values were lower than normal, while the thyrotropin (TSH) (2.33 uIU/mL), free T3 (FT3) (1.62 pmol/L), and free T4 (FT4) (11.39 pmol/L) values were normal. These values indicate a TBG partially deficient phenotype. Using PCR amplification and direct sequencing of the target gene, a missense mutation in exon 4 of the Serpina7 gene was found in the patient and the father, and the nucleic acid variant was C.909 (exon 4) g > T; the patient was heterozygous and the father was hemizygous. The literature search retrieved a total of 45 studies, most of which were related to mutations in the Serpina7 gene. The mutation locations included exons, introns, enhancers and promoters, with exons the predominant location. A total of 49 variants of the Serpina7 gene were identified. Serpina7 C.909G (P.L303F) is a mutation acquired from the father by X-linked recessive inheritance. The main clinical features of TBG deficiency patients are low serum T4, T3 and TBG levels, normal TSH, FT3 and FT4 levels, and no clinical manifestations.

Medications and Food Interfering with the Bioavailability of Levothyroxine: A Systematic Review.

Levothyroxine is a common prescribed drug. Many medications and food, however, can interfere with its bioavailability. The aim of this review was to summarize the medications, food and beverages that interact with levothyroxine and to assess their effects, mechanisms and treatments. A systematic review on interfering substances that interact with levothyroxine was performed. Web of Science, Embase, PubMed, the Cochrane library, grey literature from other sources and the lists of references were searched for human studies comparing the levothyroxine efficacy with and without interfering substances. The patient characteristics, drug classes, effects and mechanism were extracted. The NHLBI study quality assessment tools and the JBI critical appraisal checklist were used to assess the quality of included studies. A total of 107 articles with 128 studies were included. Drugs interactions were revealed in calcium and iron supplements, proton pump inhibitors, bile acid sequestrants, phosphate binders, sex hormones, anticonvulsants and other drugs. Some food and beverage could also induce malabsorption. Proposed mechanisms included direct complexing, alkalization, alteration of serum thyroxine-binding globulin levels and acceleration of levothyroxine catabolism via deiodination. Dose adjustment, administration separation and discontinuation of interfering substances can eliminate the interactions. Liquid solutions and soft-gel capsules could eliminate the malabsorption due to chelation and alkalization. The qualities of most included studies were moderate. Lots of medications and food can impair the bioavailability of levothyroxine. Clinicians, patients and pharmaceutical companies should be aware of the possible interactions. Further well-designed studies are needed to provide more solid evidence on treatment and mechanisms.

Identification of Mutations in the Thyroxine-Binding Globulin (TBG) Gene in Patients with TBG Deficiency in Korea.

Thyroxine-binding globulin (TBG) is a major transporter protein for thyroid hormones. The serpin family A member 7 (SERPINA7) gene codes for TBG, and mutations of the SERPINA7 gene result in TBG deficiency. Although more than 40 mutations have been reported in several countries, only a few studies of TBG deficiency and SERPINA7 gene mutation have been performed in Korea. The aim of this study is to review the clinical presentations and laboratory findings of patients with TBG deficiency and to investigate the types of SERPINA7 gene mutation. Five unrelated Korean adults with TBG deficiency attending endocrinology clinic underwent SERPINA7 gene sequencing. Four patients harbored a SERPINA7 gene mutation. Serum thyroid hormones, anti-microsomal antibodies, and TBG were measured. Genomic DNA was extracted from whole blood. All exons and intron-exon boundaries of the TBG gene were amplified and sequencing was performed. Two patients were heterozygous females, and the other two were hemizygous males. One heterozygous female had coexisting hypothyroidism. The other heterozygous female was erroneously prescribed levothyroxine at a local clinic. One hemizygous male harbored a novel mutation, p.Phe269Cysfs*18, which caused TBG partial deficiency. Three patients had the p.Leu372Phefs*23 mutation, which is known as TBG-complete deficiency Japan (TBG-CDJ) and was also presented in previous mutation analyses in Korea. This study presents four patients diagnosed with TBG deficiency and provides the results of SERPINA7 gene sequencing. One novel mutation, p.Phe269Cysfs*18, causing TBD-partial deficiency and three cases of TBG-CDJ were demonstrated. It is necessary to identify TBG deficiency to prevent improper treatment. Also, sequencing of the SERPINA7 gene would provide valuable information about the TBG variants in Korea.

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.

P1554AEFFECT OF HAEMODILUTION ON THYROID FUNCTION BEFORE AND AFTER HAEMODIALYSIS IN PATIENT WITH END-STAGE RENAL DISEASE

Abstract Background and Aims To study the factors involved in the low thyroid hormones in end - stage renal disease (ESRD), we compared thyroid function before and after hemodialysis (HD). Method The serum free thyroxine (fT4), free triiodothyronine (fT3), and thyroid - simulating hormone (TSH), thyroxine binding globulin (TBG) and thyroglobulin (Tg) levels were measured before and after HD in 12 patients with chronic glomerulonephritis (CGN, age; 48.7 ± 11.8 [mean ± SD]) and 11 patients with diabetic nephropathy (DN, age; 57.6 ± 6.5), comparing with controls (n = 13, age; 40.9 ± 11.3). Results The serum fT4, fT3 and TBG levels were low before HD but increased almost in parallel with the increase in hematocrit and albumin levels after HD in both ESRD groups. The serum TSH level was high before HD but decreased after HD and Tg level remained almost unchanged. In DN, serum fT4 levels was almost the same, but fT3 levels was lower with slightly higher TSH level, compared with CGN. Conclusion Significantly lower fT4, fT3 and TBG levels in ESRD before HD seemed to be due to hemodilution and almost corrected after HD. The TSH level was promptly normalized with elevated fT4, and Tg levels remained unchanged probably due to the balance between corrected hemodilution and rapid response to decreased TSH stimulation. It may better to evaluate thyroid function after HD in ESRD. Accelerated senile changes were suggested in DN.

Exposure to DBP and High Iodine Aggravates Autoimmune Thyroid Disease Through Increasing the Levels of IL-17 and Thyroid-Binding Globulin in Wistar Rats

Autoimmune thyroid disease (AITD) is the most common autoimmune disease that causes hypothyroidism. High iodine is a well-known factor that can induce thyroid disorders, including Hashimoto's thyroiditis, one of the main types of AITD. Recent epidemiological studies have indicated that phthalates, especially di-n-butyl phthalate (DBP) may induce thyroid disease. In this study, we aim to determine the effects and underlying mechanisms of high iodine and/or DBP exposure on AITD. Female Wistar rats were modeled with thyroglobulin and exposed to high iodine and/or DBP. We investigated histopathological changes in the thyroid and measured thyroid hormone levels in serum to assess thyroid function. In the thyroid and liver, we detected oxidative stress, proinflammatory factors (IL-1β, IL-6, and IL-17) and the activation of activator protein 1 (AP-1), a transcription factor that is related to the synthesis of the thyroxine-binding globulin (TBG) and the activation of Th17. After blocking AP-1 with SP600125, we detected TBG and the Th17 related cytokines (IL-6 and IL-17). The data showed that thyroid damage and the alteration of thyroid hormones were greater when the rats were exposed to both high iodine and DBP. Coexposure to DBP and high iodine enhanced the activation of AP-1 in the liver and thyroid, and induced an increase in the levels of TBG in serum and IL-17 in the thyroid. Blocking AP-1 activation prevented the increase of TBG and IL-17. The results indicate that high iodine and/or DBP exposure exacerbated AITD through altering TBG levels in serum and aggravating IL-17 in the thyroid.

Thyroid Function Tests During First-trimester of Pregnancy: A Review of Literature

This literature review was conducted to summarize the main points of maternal thyroid function tests, with particular attention in the first trimester of pregnancy which accompanied with significant biochemical and metabolic alteration. The evaluation of thyroid function of either hyperthyroidism and hypothyroidism should be assessed by determination of serum Thyroid Stimulating Hormone (TSH), Thyroxine (T4), Triiodothyronine (T3), Iodine and Thyroid Autoantibodies. Glomerular filtration rate is increased during pregnancy; therefor iodine deficiency should be evaluated during the pregnancy to prevent hypothyroidism. The role which can be played by Human Chronic Gonadotropin (hCG) on stimulating the thyroid gland to become over-active was investigated. Serum level ofthyroglobulin (Tg) and Thyroxin Binding Globulin (TBG) should be assessed for proper assessments of thyroid gland during pregnancy. Thyroid function tests during first-trimester of pregnancy and particularly the reference interval for thyroid function tests for pregnant women in each region has to be established, to prevent mis-diagnosis and irreversible mental and physical adverse affect for growing fetus.

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.

Unequal Concentrations of Free T3 and Free T4 after Ultrafiltration

Ultrafiltration is a standard method for separating free T3 and free T4 from serum proteins and protein-bound hormone (1)(2). It is expected that free T3 and free T4 in aqueous solutions will accompany water as water moves across semipermeable membranes, a process that results in equal concentrations of free T3 and free T4 in the aqueous solutions on opposite sides of semipermeable membranes after ultrafiltration. The movements of free thyroid hormones through semipermeable membranes have not been compared to the movement of water, nor have the concentrations of free hormones on opposite sides been determined in the absence of hormone-binding proteins. We report experiments with 4 different ultrafiltration devices to determine the movements of 3H2O, 125I-T3, and 125I-T4 across semipermeable membranes in a biologically relevant protein-free aqueous solution. A pool of normal human serum was obtained (Equitech-Bio). Serum thyroxine-binding globulin, transthyretin, albumin, total protein, total T4, dialyzable (free) T4, and thyroid-stimulating hormone were within their respective reference intervals (Quest Diagnostics). Serum pH was controlled at 7.4 by adding HEPES …

The T4/TBG ratio in healthy subjects and in patients with disorders of thyroid function: correlation with FT4 concentrations

Summary: The proportion of free hormones can be estimated in the presence of protein-bound hormones by a variety of direct assay approaches or by a two test strategy to calculate a free hormone »index«. The T4/TBG ratio, determined from measurements of total thyroxine (TT4) and thyroxine-binding globulin (TBG) concentrations, is an appropriate index with improved diagnostic accuracy compared with T4. In this study, we calculated the T4/TBG ratio after determining serum TT4 and TBG by radioimmunoassay (INEP, SCG) in euthyroid persons (n=102), in patients with hypothyrosis (n=33) and hyperthyrosis (n=66), as well as in healthy pregnant women (n=346). The reference range for each group of patients was determined. Values obtained for the T4/TBG ratio in healthy subjects varied from 2.1 to 4.4. They were lower in hypothyrosis (0.5 ’2.2) and elevated in hyperthyrosis (4.7–13.1). The reference intervals of the T4/TBG ratio were also determined for each trimester of pregnancy. A significant correlation was obtained between the values for T4/TBG ratio and FT4 concentration, determined by the two-step radioimmunoassay (CIS-bio international, France), in healthy subjects and patients with thyroid disorders (r=0.93), as well as during pregnancy (0.59). In conclusion, we determined reference intervals for the T4/TBG ratio, confirming its practical usefulness in the assessment of thyroid function.

Assay performance and clinical validation of a radioimmunoassay for serum thyroxine-binding globulin

A radioimmunoassay for the quantitation of serum thyroxine-binding globulin (TBG), RIA TBG (PEG) - INEP, was formed and characterised. Test sensitivity was found to be favorable (2.0 mg/L). The highly satisfactory precision of the assay was reflected in the low coefficients of variation (less than 5%) found for both intra- and interassay precision at three concentrations. Non-specific binding of the labeled antigen was less than 2% of the total binding. Linearity of the assay within the range of the standard curve (0-80.0 mg/L) was excellent (r =0.99) and the analytical recovery of TBG added to serum ranged from 91 to 115%. Reproducibility was checked by determining the concentration of TBG in samples of sera over a period of 32 days from the day of antigen iodination and F&lt;Ftab 0.05, F0.05 7, 32 = 2.31. The assay was standardized for accuracy using Lyphochek Immunoassay Controls (Bio-Rad). A significant correlation was obtained between RIA TBG (PEG) and the Kodak Amerlite TBG Assay (r = 0.84; n = 25). The presented results show that RIA TBG (PEG) is a sensitive, precise and reliable method for determination of TBG in human sera. Assay reference ranges were established for sera from various subjects: euthyroid adults, hypothyroid and hyperthyroid patients and in healthy pregnant women.

The hypothalamic-pituitary-thyroid axis in preterm infants; changes in the first 24 hours of postnatal life.

The purpose of this study was to measure serum T4, free T4, TSH, T3, rT3, T4 sulfate, and thyroxine binding globulin at four time points within the first 24 h of life (cord and 1, 7, and 24 h) in infants between 24 and 34 wk gestation. The infants were subdivided into gestational age groups: 24-27 wk (n = 22); 28-30 wk (n = 26); and 31-34 wk (n = 24). The TSH surge in the first hour of postnatal life was markedly attenuated in infants of 24-27 wk gestation [8 compared with 20 (28-30 wk) and 23 mU/liter (31-34 wk)]. T4 levels in the most immature group declined over the first 24 h, whereas levels increased in the more mature groups [mean cord and 24-h levels: 65 and 59 (NS) vs. 70 and 84 (P < 0.002) vs. 98 and 125 (NS) nmol/liter]. Free T4 and T3 showed only small, transient increases in the most immature group and progressively larger and sustained increases in the other gestational groups. rT3 and T4 sulfate levels in cord serum were higher in the most immature infants, and in all groups levels decreased initially and then variably increased. The features of a severely attenuated or failed hypothalamic-pituitary-thyroid response to delivery critically define this 24- to 27-wk group as distinct from more mature preterm infants.

Comparative analytical evaluation of thyroid hormone levels in pregnancy and in women taking oral contraceptives: a study from an iodine deficient area

Increase of serum thyroxine binding globulin (TBG) resulting from estrogen action may lead to problems in thyroid diagnostics. The aim of the present study was to define the most diagnostically reliable thyroid parameters in women exposed to differentially elevated estrogens. Sera of three groups of healthy women were analyzed: women taking no medicine (controls), those taking oral contraceptives and pregnant women (in weeks 16 or 32 of gestation). All women involved in the study lived in a moderately iodine-deficient geographical area. Thyroid stimulating hormone (TSH), TBG, total thyroxine (T4), total triiodothyronine (T3) and free T3 were determined and free T4 indices (total T4 × T3 uptake; total T4/thyroxine binding capacity (TBC); total T4/TBG) were calculated. Free T4 was measured simultaneously with a one-step T4-analog enzyme-linked immunosorbent assay (ELISA), a labeled T4 antibody radioimmunoassay (RIA), and a two-step microparticle enzyme immunoassay (MEIA). Estrogen-dependent differences were found in all investigated parameters; however, they remained in the reference interval for TSH, total T4 × T3 uptake, total T4/TBC, free T3 and free T4 MEIA. It was concluded that simultaneous estimations of free T4 and free T3 should follow a primary TSH measurement. The necessity of a distinct reference range has emerged for free thyroid hormones in midterm and late pregnancy as well as in the use of oral contraceptives, especially in iodine-deficient areas.

Increased serum reverse triiodothyronine levels at diagnosis of hepatocellular carcinoma in patients with compensated HCV-related liver cirrhosis.

The aim of this study was to investigate changes in thyroid hormone metabolism in relation to the development of hepatocellular carcinoma (HCC) in patients with HCV-related liver cirrhosis. The study group (Group A) comprised 31 patients (25 M, 6 F; median age 62.1 years, range 54.0-81.5 years) affected by HCV-related liver cirrhosis with superimposed HCC. Acute and chronic systemic disease, other than cirrhosis, inducing 'euthyroid sick syndrome' was excluded in all patients. Serum TSH, FT4, FT3, rT3, and thyroxine-binding globulin (TBG) levels were retrospectively evaluated in frozen aliquots drawn at the time of tumour diagnosis and every 6 months for 3-7 years before HCC diagnosis. The control group (Group B) comprised 29 patients affected by HCV-related liver cirrhosis without HCC, matched for sex, age and grade of liver dysfunction. At the time of HCC diagnosis, all patients in Group A were euthyroid with serum TSH, FT4, FT3 and TBG values not significantly different from those of cirrhotic patients of Group B. However, at diagnosis Group A patients had serum rT3 values that were significantly higher than those in Group B (35.0 ng/dl, range 12.0-162.0 vs. 19.0 ng/dl, range 10.0-51.0; Group A vs. Group B; P < 0.001). Serum rT3 values above the normal range were found in 12 patients in Group A (38.7%) but in only one of the patients from Group B (3.4%) (chi2 10.2; P = 0.001). The serum rT3 levels were not significantly correlated to the Child grade of liver cirrhosis (rho 0.1; P = 0.5). The intrasubject analysis demonstrated that a significant increase in serum rT3 levels occurred at the time of HCC diagnosis but serum FT4, FT3 and TSH values did not change significantly. A receiver operating curve (ROC) demonstrated that a 6-monthly increase in serum rT3 levels of at least +22.5% identified patients with HCC with a diagnostic accuracy of 81.7%. Our study has demonstrated that development of hepatocellular carcinoma is accompanied by a significant increase in serum rT3 levels in patients with low-grade HCV-related liver cirrhosis who had no other illness causing the 'euthyroid sick syndrome'.

Complete Thyroxine-Binding Globulin (TBG) Deficiency in Two Families without Mutations in Coding or Promoter Regions of the TBG Genes: In Vitro Demonstration of Exon Skipping

Inherited thyroxine-binding globulin (TBG) deficiency is caused by mutations in the TBG gene located on the X-chromosome. We now describe two families (K and H) with X-linked complete TBG deficiency without mutations in the coding or promoter regions of the TBG gene. The propositi of both families presented with euthyroid hypothyroxinemia and were found to have undetectable TBG in serum. Affected females had approximately half the normal serum TBG concentration except for one woman who also had undetectable TBG (family H). All four of her children (two boys and two girls) were affected. Affected members of family K had no mutations in any of the five exons or in the minimal promoter region of the TBG gene. However, a G to A substitution, five base pairs downstream from exon 3, was associated to the phenotype of TBG deficiency (TBG-Jackson) and was not present in 100 normal alleles. In contrast to individuals without this mutation, no TBG mRNA could be detected in fibroblasts of the propositus, expressing solely TBG-Jackson. In vitro transcription of genomic DNA containing the mutant intron in an exon trapping system showed that this mutation, reducing the consensus value on the 5′ donor splice site, affects the normal splicing process. The transcript of TBG-Jackson lacks exon 3 and is unstable. The deduced amino acid sequence has a frameshift and an early stop codon at position 325. Affected subject of family H had no mutations in the TBG gene including all exons, all introns, the minimal promoter, and the 3′ untranslated sequence. However, an intragenic A/G polymorphism (125 bp upstream from exon 2) was identified. It allowed us to confirm a cosegregation of the phenotype to the TBG gene and to show that the single female with complete TBG deficiency was homozygous for the polymorphic TBG allele. The cause of TBG deficiency in this family remains unknown.

Desenvolvimento de ensaio imunofluorométrico para a medida da globulina ligadora de tiroxina (thyroxine-binding globulin, TBG) e sua aplicação em casos de deficiência desta proteína

A globulina ligadora de tiroxina (thyroxine-binding globulin, TBG) é a principal transportadora de hormônios tiroidianos no soro. Variações na concentração sérica de TBG determinam variações proporcionais nas concentrações séricas totais de T4 e T3, sem implicar alterações de função, desde que a fração livre permaneça normal. Várias condições clínicas comuns levam a alterações significativas nos níveis de TBG, sendo as variações mais importantes devidas a defeitos genéticos. Como a TBG é codificada por gene localizado no cromossomo X, os defeitos se manifestam mais facilmente no sexo masculino. Descrevemos o desenvolvimento de ensaio imunofluorométrico para a medida de TBG com base em anticorpos monoclonais, sendo um desenvolvido em nosso laboratório e outro comercial. O método apresenta sensibilidade de 0,8mg/l e coeficientes de variação intra e interensaio inferiores a 10%. O estudo comparativo com método comercial mostrou alta correlação (r = 0,93; n = 48), sendo os valores normais obtidos de 10mg/l a 29mg/l. Estudamos também 20 indivíduos portadores de deficiência congênita de TBG, 19 homens e uma mulher, que apresentavam valores normais de TSH e baixos de T4 total; em todos eles os níveis de TBG foram indetectáveis. Já os níveis de T4 livre medidos por método indireto em 16 desses indivíduos mostraram-se elevados em todos, ao passo que, quando medidos por método direto pós-diálise nos quatro restantes, mostraram-se normais. Nossos resultados reforçam a necessidade prática da disponibilidade de ensaio para a medida de TBG para esclarecimento e definição diagnóstica de alguns casos especiais, principalmente quando o ensaio de T4 livre direto, pós-diálise, não é disponível.

Thyroxine Dosing for Women on Postmenopausal Estrogen Therapy

When a euthyroid woman begins postmenopausal estrogen therapy, serum thyroxine-binding globulin (TBG) and total thyroxine (T4) increase; however, the

Pregnancy and iodine.

Hormonal changes and metabolic demands during pregnancy result in profound alterations in the biochemical parameters of thyroid function. For thyroid economy, the main events occurring during pregnancy are a marked increase in serum thyroxine-binding globulin levels; a marginal decrease in free hormone concentrations (in iodine-sufficient areas) that is significantly amplified when there is iodine restriction or overt iodine deficiency; a frequent trend toward a slight rise in basal thyrotropin (TSH) values between the first trimester and term; a transient stimulation of the maternal thyroid gland by elevated levels of human chorionic gonadotropin (hCG) resulting in a rise in free thyroid hormones and decrement in serum TSH concentrations during the first trimester; and finally, modifications of the peripheral metabolism of maternal thyroid hormones. Together, metabolic changes associated with the progression of gestation in its first half constitute a transient phase from preconception steady state to pregnancy steady state. In order to be met, these metabolic changes require an increased hormonal output by the maternal thyroid gland. Once the new equilibrium is reached, increased hormonal demands are maintained until term, probably through transplacental passage of maternal thyroid hormones and increased turnover of maternal thyroxine (T4), presumably under the influence of the placental (type 3) deiodinase. For healthy pregnant women with iodine sufficiency, the challenge of the maternal thyroid gland is to adjust the hormonal output in order to achieve the new equilibrium state, and thereafter maintain the equilibrium until term. In contrast, the metabolic adjustment cannot easily be reached during pregnancy when the functional capacity of the thyroid gland is impaired because of iodine deficiency. The ideal dietary allowance of iodine recommended by World Health Organization (WHO) is 200 microg of iodine per day for pregnant women. In conditions with iodine restriction, enhanced thyroidal stimulation is revealed by relative hypothyroxinernia and goitrogenesis. Goiters formed during gestation may only partially regress after parturition. Pregnancy, therefore, represents one of the environmental factors that may help explain the higher prevalence of goiter and thyroid disorders in women compared with men. An iodine-deficient status in the mother also leads to goiter formation in the progeny and neuropsycho-intellectual impairment in the offspring. When adequate iodine supplementation is given early during pregnancy, it allows for the correction and almost complete prevention of maternal and neonatal goitrogenesis. In summary, pregnancy is accompanied by profound alterations in the thyroid economy, resulting from a complex combination of factors specific to the pregnant state, which together concur to stimulate the maternal thyroid machinery. Increased thyroidal stimulation induces, in turn, a sequence of events leading from physiological adaptation of the thyroidal economy observed in healthy iodine-sufficient pregnant women to pathological alterations affecting both thyroid function and the anatomical integrity of the thyroid gland, when gestation takes place in conditions with iodine restriction or deficiency: the more severe the iodine deficiency, the more obvious, frequent, and profound the potential maternal and fetal repercussions.

Thyroidopathies

Pregnancy affects thyroid physiology in many ways: (a) The renal iodide clearance rate is increased, hence iodine requirements increase. (b) The fetal requirements for thyroid hormones and iodide are an additional problem. (c) Serum thyroxine-binding globulin increases, thus producing an increase in the levels of total T4 and T3. (d) Chorionic gonadotropin has a thyroid-stimulating activity. This may be compensated for by a decrease in TSH, but in some cases gestational thyrotoxicosis occurs. (e) Thyroid autoimmunity usually subsides during pregnancy, but may rebound a few months after parturition, and postpartum thyroiditis may occur. Because maternal antithyroid autoantibodies cross the placenta readily, fetal and neonatal hyperthyroidism (or hypothyroidism) may develop. Pre-existing thyroid diseases are influenced. Nontoxic goiter increases in size. Iodine and/or thyroxine may be required. Graves' disease may remit. If present, antithyroid drugs should be given in small doses, and quite often they may be stopped altogether. Hypothyroid patients may require a larger T4 dose.

Blood biochemistry and endocrinology in the human fetus between 11 and 17 weeks of gestation

Fetal blood was obtained in 35 normal pregnancies undergoing termination for psychosocial reasons between 11 and 17 weeks of gestation. Biochemical and endocrinological analyses were performed on each sample including concentrations of urea, creatinine, β-microglobulin total protein, electrolytes, enzymes, alpha-fetoprotein (AFP), human chorionic gonadotrophin (HCG), thyroid stimulating hormone (TSH), thyroxin binding globulin (TBG), total thyroxin (TT4) and free thyroxin (FT4). The results were compared with values in maternal serum obtained at the same time. Fetal serum contained significantly higher concentrations of iron, β-microglobulin, alkaline phosphatase (ALP), aspartate amniotransferase (AST), AFP, HCG and TSH and lower concentration of total protein, TBG and TT4 than maternal serum. Significant positive linear relationships were found between gestational age and the concentration of fetal serum total protein, ALP, TBG and FT4. Significant negative linear relationships were observed between gestational age and fetal serum β-microglobulin and iron concentration. There were no significant correlations between fetal and maternal values. These data indicate that fetal blood biochemistry is not directly related to placental transfer and that the proteins and enzymes found inside the gestational sac are essentially of feto-placental origin with minimal contribution from the maternal protein metabolism. The comparison of coelomic fluid composition at 10-13 weeks with that of fetal serum at 11-17 weeks suggests that the anatomical changes in the human materno-fetal interface architecture between the early and late pregnancy periods could have a direct impact on materno-fetal transfer pathways.