Binding Capacity Of Thyroxine-binding Globulin Research Articles

Thyroid Dysfunction as a Mediator of Organochlorine Neurotoxicity in Preschool Children

Background: Exposure to organochlorine compounds (OCs) can alter thyroid function in humans, and hypothyroidism during early life can adversely affect a child’s neurodevelopment.Objectives: In this study we aimed to assess the relationship between developmental organochlorine exposures and thyroid function and the relationship between thyroid function and subsequent neurodevelopment.Methods: A population-based birth cohort of 182 children was followed annually up to 5.5 years of age. The assessments included OC concentrations in maternal pregnancy serum and milk, clinical thyroid parameters in maternal and cord serum, and subsequent neuropsychological outcomes of the child, along with sociodemographic cofactors. Resin triiodothyronine uptake ratio (T3RU) was also assessed as an estimate of the amount of thyroxine-binding globulin (TBG) sites unsaturated by thyroxine. The T3RU is high in hyperthyroidism and low in hypothyroidism.Results: The findings showed consistent inverse and monotonic associations between organochlorine exposure and T3RU after covariate adjustments. We observed no associations with other thyroid parameters. T3RU was positively associated with improved performance on most of the neuropsychological tests. For other thyroid parameters, the findings were less consistent.Conclusions: The results suggest that OC exposures may decrease the T3RU during early life, which is a proxy measure of the binding capacity of TBG. In addition, minor decreases of the thyroid function may be inversely associated with a child’s neurodevelopment.

Increase in thyroxine-binding globulin (TBG) in lysinuric protein intolerance.

The common occurrence of increased serum PBI concentration in patients with lysinuric protein intolerance (LPI) was elucidated by further studies. The reason was found to be an increase in the concentration of thyroid binding globulin (TBG), concomitantly with an increase in the binding capacity of TBG. The concentrations of serum thyroxine and triiodothyronine were elevated, whereas the free thyroxine index remained normal. The free triiodothyronine index was slightly increased. The binding capacity of thyroid hormone binding pre-albumin (TBPA) was significantly decreased. The concentrations of reverse triiodothyronine (3,3',5'-T3) and of 3,3'-diiodothyronine were normal. In all patients serum lactic acid dehydrogenase activities and ferritin concentrations were elevated. The reason for the almost constant increase in TBG remains obscure. It may be related to the primary disorder of LPI, a defect in diaminoacid transport.

Thyroid hormone binding in nonthyroid illness

The binding of the thyroid hormones, L-thyroxine (T 4) and L-triiodothyronine (T 3), was examined in eight sera obtained from patients with severe illness and the results compared to those obtained in a concurrently studied normal serum pool. In these eight sera, the values for percent free T 4 (%FT 4) and free T 3 (%FT 3) measured by dialysis were distinctly increased. The calculated values for the absolute concentration of FT 4 in six of the eight sera were increased relative to the value in the normal pool and in all eitht sera were greatly underestimated by a free T 4 index based on an in vitro T 3-uptake test. By contrast, the absolute concentration of free T 3 was distinctly increased in only one of the eight sera and this increase was reflected in the free T 3 index. Mixing of the normal serum pool with seven of the eight sera produced values for %FT 4 that significantly exceeded those in normal pool diluted with buffer so that the resulting values for thyroxine-binding globulin (TBG) binding capacity were equivalent to those in the serum mixtures. By contrast, values for %FT 3 in these sera did not differ in a consistent manner from those in the normal pool diluted with buffer to equivalent values for TBG binding capacity. Ultrafiltrates prepared from each of the eight sera, when employed in place of buffer as diluent for serum in the dialysis method for measuring %FT 4, did not affect the %FT 4 in the normal serum pool. Likewise, immunoglobulin concentrates prepared from three sera were also without effect on the %FT 4 in the normal pool. We conclude that there is present in the serum of some patients with severe nonthyroid illness either a nonultrafilterable binding inhibitor or a protein-protein interaction that interferes with T 4-binding to a greater extent than T 3-binding, thereby resulting in a value for %FT 4 that is greater than can be accounted for by a decrease in TBG. Such a phenomenon might contribute to the underestimation by the in vitro T 3-uptake test of the %FT 4.

Thermal inactivation of thyroxine-binding globulin for direct radioimmunoassay of triiodothyronine in serum.

ABSTRACT A new radioimmunoassay procedurefor triiodothyronine (T3) is described. The methoduses unextracted serum at a 1:4 dilution. The novel feature of the process is that preincubation and incubation with isotope take place at 60 C. At this temperature the binding capacity of thyroxine-binding globulin (TBG) is virtually eliminated and the antigen-antibody reaction is greatly accelerated.Separation of antibody-bound hormone from freehormone is effected by polyethylene glycol solution. By plotting the standard curve on Probability × logarithmic paper, the curve is linear. Logit × log plots give the same results and facilitate calculation of data by a simple computer program. Sera of 31 normal individuals showed a meanvalue (±sd) of 189 ± 30 ng per 100 ml. Fourteen clinically thyrotoxic individuals had T3 values of 838 ± 398 ng per 100 ml and 19 clinically myxedematous patients had T3 values of 47 ± 39 ng per100 ml. These values were confirmed by using several different antisera and by performing the rad...

The effect of alteration of thyroxine binding capacity on the dialyzable and absolute fractions of triiodothyronine in circulation.

ABSTRACT In order to determine the effect of alterations in binding capacity of thyroxine binding globulin (TBG) on triiodothyronine (T3) metabolism, studies were conducted in 10 patients with idiopathically low (7 subjects) or elevated (3 subjects) TBG levels and 10 subjects given norethandrolone (7 male subjects) or oestrogen (3 female subjects). Measurements of serum thyroxine (T4) concentration, maximal T4 binding capacity, serum T3 concentration and per cent dialyzable T3 were conducted. Serum T3 was measured both by chemical and radioimmunoassay methods. In patients with idiopathically low TBG, the mean serum T4 concentration was low (2.4 μg/100 ml), the mean serum T3 level low (55 ng/100 ml), the mean per cent dialyzable T3 increased (0.52%), and the calculated free T3 concentration normal (186 pg/100 ml). In patients with idiopathically high TBG levels the mean T4 concentration was high (10.3 μg/100 ml), the mean T3 level slightly elevated (127 ng/100 ml), the% dialyzable T3 low (0.10%) and the calculated free T3 concentration low normal (123 pg/100 ml). The correlation coefficient between the per cent dialyzable T3 and maximal TBG binding capacity in the 20 subjects was 0.68, a value significant at the P < 0.01 level. Thus, alterations in binding capacity of TBG seem to influence T3 and T4 metabolism similarly; the inverse relationship between the % of dialyzable hormone and total hormone concentration tends to keep the absolue levels of free hormones stable.

THYROXINE-BINDING GLOBULIN DEFICIENCY AND ASSOCIATED NEUROLOGICAL DEFICIT

Thyroxine-binding globulin deficiency and significant mental deficiency were found to be associated in four males of one family, all of whom had absence of serum thyroxine-binding globulin (TBG). In 18 family members studied, two additional females had a decreased thyroxine (T4) binding capacity of TBG but were not retarded. No other specific cause of the mental retardation could be elicited. The hereditary nature of TBG deficiency and the associated neurological and mental defects could suggest that the gene loci for these disorders are "near" to each other, although no evidence is available to verify this possibility. The spectrum of this disorder should now be widened to include mental retardation as one of its features.

Thyroid function in the premature and the full term newborn.

ABSTRACT Total and free serum thyroxine, plasma thyrotrophin (TSH) levels and, in some cases, the binding capacity of thyroxine-binding globulin (TBG) were measured in normal and premature newborns. In both groups, an acute release of TSH was observed in the first few hours of life, but this was prolonged over a period of 10 days in the premature newborns. The release of TSH induced, in both groups, an increase of total and free serum thyroxine (T4), reaching thyrotoxic levels. The TBG binding capacity, however, remains normal. This thyroid hyperactivity at birth reveals an important reserve of TSH in the perinatal period and the great metabolic needs of the foetus on the first day of life.

Study of Four New Kindreds with Inherited Thyroxine-Binding Globulin Abnormalities POSSIBLE MUTATIONS OF A SINGLE GENE LOCUS

Five families with inherited thyroxine-binding globulin (TBG) abnormalities were studied. On the basis of serum thyroxine (T(4))- binding capacity of TBG in affected males, three family types were identified: TBG deficiency, low TBG, and high TBG capacity. In all families evidence for X-linked inheritance was obtained and in one family all criteria establishing this mode of inheritance were met. Only females were heterozygous, exhibiting values intermediate between affected males and normals. Overlap in heterozygotes was most commonly encountered in families with low TBG. QUANTITATIVE VARIATION IN THE SERUM CONCENTRATION OF FUNCTIONALLY NORMAL TBG WAS DEMONSTRATED BY: (a) failure of serum from TBG-deficient subjects to react with anti-TBG antibodies; (b) normal kinetics of T(4) and triiodothyronine-binding to TBG in sera from subjects with low TBG and high TBG capacity; (c) concordance of estimates of TBG concentration by T(4) saturation and by immunological methods; and (d) normal rate of heat inactivation of TBG. No abnormalities in serum transport of cortisol, testosterone, aldosterone, or thyroxine bound to prealbumin could be detected. These observations suggest that all the TBG abnormalities thus far observed reflect mutations at a single X-linked locus involved in the control of TBG synthesis.

THYROID FUNCTION IN ACROMEGALY

Thyroid-function studies were performed in 12 patients with active acromegaly. 1 patient had thyrotoxicosis, the rest were considered euthyroid although 3 of them had abnormal thyroid scans. All patients had a normal serum thyroid-stimulating-hormone (T.S.H.) level. The euthyroid group had renal and thyroid iodide clearances significantly greater than normal (P < 0·05 and P < 0·01 respectively). The absolute iodide uptake (A.I.U.) and 21/2-hour radioiodine uptake by the thyroid were also significantly greater than normal (P<0·05) and the plasma-inorganic-iodide (P.I.I.) was in the low normal range. The maximal binding capacity of thyroxine-binding prealbumin (T.B.P.A.) was increased and the maximal binding capacity of thyroxine-binding globulin (T.B.G.) was normal during the early years of active acromegaly. However, considering the duration of active disease (range 4-30 years) a significant linear diminution (P < 0·05) of both T.B.P.A. and T.B.G. could be demonstrated with time.

The binding capacity of thyroxine-binding globulin in cerebrospinal fluid.

ABSTRACT The binding capacity of thyroxine-binding globulin (TBG), and total and dialysable thyroxine in the cerebrospinal fluid (CSF) and in serum have been estimated in 13 euthyroid patients with normal and elevated CSF protein and in 5 hyperthyroid and 5 hypothyroid patients. In the normal group, the mean value of TBG in CSF was found to be 2.7 ng/ml and 207 ng/ml in serum. TBG in CSF in relation to the total protein content was found to be much higher than TBG in the serum in relation to the total serum protein. In the euthyroid patients with elevated CSF protein TBG was also increased but not proportional to the increase in the protein concentration. In the hyperthyroid patients TBG in CSF was decreased and was lower than the elevated total thyroxine values. Dialysable thyroxine, however, showed only a moderate increase indicating that proteins other than TBG must bind a considerable part of total thyroxine in CSF in hyperthyroid patients. In myxoedema TBG was found to be elevated in proportion to the slightly elevated CSF protein content. It is concluded that TBG in normal CSF seems to be the physiologically most important thyroxine-binding protein.

Thyroid overactivity and TBG deficiency simulating "T3 hyperthyroidism".

A case of toxic nodular goiter with a deficiency of thyroxine-binding globulin (TBG) is described. Laboratory test results fulfilled the usually suggested criteria for the diagnosis of “T3 hyperthyroidism” except for the low TBG binding capacity. In the presence of reduced TBG binding capacity, serum T4 is low, since thyroxine is predominantly bound to this carrier. The diagnosis of T3 hyperthyroidism should not be made without proof of normal levels of TBG.

Radioimmunoassay of human thyroxine-binding globulin (TBG).

ABSTRACT A radioimmunoassay for human thyroxine-binding globulin (TBG) has been developed. It employs highly purified TBG as an antigen, an antiserum prepared against the TBG, and 125I-labeled TBG. The assay is specific, being unaffected by sera from animals or by human serum proteins other than TBG. It can detect less than 1 ng of TBG. TBG concentration in sera from normal adults was found to range between 2.0 and 4.8 mg/100 ml, with a mean of 3.6. Severe cirrhosis of the liver caused a significant lowering of TBG concentration. Hypothyroidism was without apparent effect. Except in thyroid disease, TBG concentration was found to correlate with the result of the T3 resin sponge uptake test (T3RU); in hyperthyroidism the T3RU is higher than predicted from the TBG concentration and the opposite is true in hypothyroidism. In all sera tested the maximum binding capacity of TBG in whole serum for T4 was found to be proportional to the TBG content. In subjects with congenital disorders of TBG concentration, the...

Inherited decrease of the binding capacity of thyroxine-binding globulin (TBG).

ABSTRACT A family with a decrease in the binding capacity of thyroxine binding globulin (TBG) is described. The gene was probably transmitted by a female who married twice. Five subjects were considered TBG deficient, with TBG values ranging from 8.4 to 16.8 μg/100 ml. Of these subjects 2 were males and 3 females; the males had the lowest binding capacities. In addition, 1 male and 3 females had TBG values within the low normal range and were considered as possibly affected. The mode of inheritance could not be exactly defined but there were indications that it might be an autosomal dominant. The correlation of TBG to the protein-bound iodine in the serum (PBI), to the triiodothyronine uptake by Sephadex (T3-U), to the ratio between them (T3-U/PBI), and to the proportionate free thyroxine (PFT4) was strongly positive or negative. A gradual change in these variables from the affected to the unaffected subjects was observed. These correlations indicated that in normal subjects TBG is the most important factor governing the PBI and free thyroxine levels. In addition, a strong inverse and statistically significant correlation was observed between the binding capacity of TBG and that of the pre-albumin (TPBA). The difference between affected and unaffected subjects with regard to TPBA was also statistically significant.

Increased serum thyroxine-binding globulin capacity: inheritance and linkage relationships.

ABSTRACT The binding capacity of thyroxine-binding globulin (TBG) has been measured in 60 members of a kindred. The data strongly suggest X-linked inheritance of the trait for elevated TBG binding capacity. The results of blood grouping tests indicate that the X-linked Xg locus is not closely linked to the locus for increased TBG capacity.

Effect of human growth hormone on thyroidal secretion, radiothyroxine turnover and transport in man.

Human growth hormone (HGH, Raben) was administered up to 15 days in biologically effective dosage (4–8 mg/day) to 8 normal adult volunteers to investigate its effect on various thyroid indices. The thyroidal secretion rate was measured in 2 subjects; radiothyroxine turnover, thyroxine binding to serum protein carriers and serum free thyroxine levels were studied in the remaining subjects. No effects were noted on thyroidal secretion, daily thyroxine degradation rate or the serum free thyroxine levels (% or concentration) as a result of HGH administration. However, HGH resulted in slight but significant decreases in concentrations of serum proteins, PBI and the binding capacity of thyroxine-binding globulin (TBG), the trend being noted as early as 5 days after HGH. Based on the data presented it was concluded that short-term HGH administration has no physiologically significant effect on thyroxine homeostasis in man, since the slight changes in serum proteins, PBI and TBG binding capacity were associated with unaltered radiothyroxine turnover and free thyroxine levels.

Estimation of rapidly exchangeable cellular thyroxine from the plasma disappearance curves of simultaneously administered thyroxine-131-I and albumin-125-I.

A mathematical analysis of the plasma disappearance curves of simultaneously injected thyroxine-(131)I and albumin-(125)I allows the development of simple formulas for estimating the pool size and transfer kinetics of rapidly exchangeable intracellular thyroxine in man. Evidence is presented that the early distribution kinetics of albumin-(125)I can be used to represent the expansion of the thyroxine-(131)I-plasma protein complex into the extracellular compartment. Calculations indicate that approximately 37% of total body extrathyroidal thyroxine is within such exchangeable tissue stores. The average cellular clearance of thyroxine is 42.7 ml per minute, a value far in excess of the metabolic clearance of this hormone. Results of external measurements over the hepatic area and studies involving hepatic biopsies indicate that the liver is an important but probably not the exclusive component of the intracellular compartment. The partition of thyroxine between cellular and extracellular compartments is determined by the balance of tissue and plasma protein binding factors. The fractional transfer constants are inversely related to the strength of binding of each compartment and directly proportional to the permeability characteristic of the hypothetical membrane separating compartments. Appropriate numerical values for these factors are assigned. An increased fractional entrance of thyroxine-(131)I into the cellular compartment was noted in a patient with congenital decrease in the maximal binding capacity of thyroxine-binding globulin and in three patients after the infusion of 5,5-diphenylhydantoin. Decreased intracellular space and impaired permeability characteristics were observed in five patients with hepatic disease. Studies of the rate of entrance of thyroxine-(131)I and albumin-(125)I into the pleural effusion of a patient with congestive heart failure suggested that transcapillary passage of thyroxine independent of its binding protein is not a predominant factor in the total distribution kinetics of thyroxine-(131)I. The thesis is advanced that the distribution of thyroxine, both within the extracellular compartment and between the extracellular and intracellular compartments, is accomplished largely by the carrier protein and the direct transfer of thyroxine from one binding site to another. The concept of free thyroxine is reassessed in terms of this formulation.

Sex-related differences in the binding in serum of thyroid hormones.

ABSTRACT Studies were conducted to determine whether there occur any sex-related differences inthe binding of thyroid hormones in the serums of normal young adult males and females. Paper electrophoretic studies conducted in both Tris-maleate and glycine-acetate buffers revealed a higher thyroxine (T4)-binding capacity of thyroxine-binding globulin(TBG) and a lower binding capacity of T4-binding prealbumin (TBPA) in specimens from females than in those from males. Studies of the distribution of small “tracer” concentrations of 131I-labeled T4 revealed similar sex-related differences, a greater proportion being associated with TBG and a lower proportion with TBPA in serums from females. Studies were also conducted in a barbital buffer in which binding of T4 by TBPA was completely inhibited. Here, too, at standard concentrations of added T4, a greater proportion was associated with TBG in specimens from females. The resin-sponge uptake of 131I-labeled 3,5,3′- triiodothyronine was slightly, but significantly...

Polyacrylamide gel electrophoretic study on the effect of estrogen on human thyroxine-binding prealbumin.

Ethinyl estradiol was administered orally in a daily dose of 0.18-0.3mg for seven days to subjects with normal and abnormal thyroid function, and the changes of several parameters of the thyroid function during estrogen administration were investigated. The concentration and maximum T4 binding capacity of thyroxine-binding prealbumin (TBPA) were estimated by polyacrylamide gel electrophoresis. Estrogen increased the serum PBI value and the binding capacity of thyroxinebinding globulin (TBG), while it lowered Triosorb test value, elutable fraction and the concentration and binding capacity of TBPA. However, free T4 value, BMR, thyroidal 24-hour uptake of 131I and thyroidal effective half-life of 131I did not change. T4 half-life in serum was prolonged. These results show that ethinyl estradiol may have an effect at first on the metabolism of thyroxine-binding proteins. The concentration and binding capacity of thyroxine-binding proteins may increase as a whole. The fact that T4 half-life is prolonged and free T4 level stays as before in spite of the rise of PBI in estrogen administration might be due to suppressed decomposition of free T4. These results are observed equally in subjects with intact and abnormal thyroid functions, and it is concluded that these phenomena have no relation to the pituitary-thyroid system.

Effect of prednisone on thyroxine-binding proteins.

Administration of high doses of prednisone to 5 patients resulted in a progressive increase in the maximal binding capacity of thyroxine-binding prealbumin (TBPA) and a simultaneous decline in the binding capacity of thyroxine-binding globulin (TBG). In every instance the lowest TBG binding capacity reached fell below the established normal range. In 2 patients, the highest TBPA binding capacities induced by prednisone exceeded the upper normal limit. Densitometric analysis of starch gel patterns stained for protein indicated that the elevated binding capacities of TBPA were directly related to increased serum concentrations of TBPA. Since no charges in the net binding of thyroxine to plasma proteins were demonstrated by equilibrium dialysis, it appears that the rise in TBPA is effectively balanced by a reduction in the TBG binding capacity. Thus, the fall in serum PBI observed in 4 of these patients cannot be easily attributed to a primary disturbance in binding proteins. In vitro addition of glucocortic...

PHYSIOLOGICAL SIGNIFICANCE OF THYROXINE-BINDING BY PROTEINS: THE RELATIONSHIP BETWEEN CHANGES IN THYROXINE-BINDING GLOBULIN CAPACITY AND THE DAILY UTILIZATION RATE OF THYROXINE IN THE NEWBORN PIG.

SUMMARY (1) Experiments were performed on three litters of pigs (four animals in each litter) between birth and the 8th day (inclusive) of life. (2) The relation between the variation in thyroxine-binding globulin (TBG) capacity and the rate of thyroxine utilization has been taken as an indication of the ability of thyroxine production to maintain a fairly constant percentage of saturation of the TBG. (3) Dynamic changes in the interaction between the thyroid hormone and the plasma protein binding sites are shown. Changes in the binding capacity of TBG were negatively correlated with uptake of [131I]triiodothyronine by erythrocytes (r = −0·64; P &lt; 0·01) and positively correlated with the protein-bound iodine (PBI) value (r = +0·92; P &lt; 0·01). (4) The value for saturation of the plasma TBG capacity was relatively stable and amounted to 67·38 ± 5·47%. (5) The total quantity of thyroxine which has to match the variability of the protein binding site capacity was calculated to be only 13·72% of the daily production of the hormone in 8-day-old pigs. (6) The physiological implication is discussed of changes in TBG capacity resulting in an increase of the bound-thyroxine pool in relation to the daily utilization rate of the hormone.