Serum free thyroxine in thyroidal and nonthyroidal illnesses: a comparison of measurements by radioimmunoassay, equilibrium dialysis, and free thyroxine index.
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Dialysis↗
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Serum ratio of triiodothyronine to thyroxine, and thyroxine-binding globulin and calcitonin concentrations in Graves' disease and destruction-induced thyrotoxicosis.
The serum ratios of T3 to T4, and T4-binding globulin (TBG) and calcitonin concentrations were studied in cases of thyrotoxic Graves' disease and destruction-induced thyrotoxicosis. In 272 patients with Graves' disease, 209 of 240 (87%) untreated patients without complications had high T3 to T4 ratios (nanograms per micrograms) of more than 20. Six of 32 (19%) patients with Graves' disease who had complications (15 with pregnancy, 14 with increased TBG, and 3 with conditions associated with a low T3 syndrome) had high T3 to T4 ratios. Eleven of 74 (15%) patients with destruction-induced thyrotoxicosis (24 with subacute thyroiditis, 39 with postpartum transient thyrotoxicosis, and 11 with spontaneous transient thyrotoxicosis) had high T3 to T4 ratios. Patients who had serum T4 levels of more than 30 micrograms/dl and/or T3 levels of more than 800 ng/dl had Graves' disease. There was no significant correlation between the T3 to T4 ratio and activities of thyroid-stimulating immunoglobulins in thyrotoxic patients with Graves' disease who had no complications. The average serum levels of TBG in destruction-induced thyrotoxicosis and thyrotoxic Graves' disease were 20.7 +/- 4.3 micrograms/ml (mean +/- SD; n = 22), and 19.9 +/- 4.0 (n = 41), respectively, which were significantly lower than that in healthy subjects (22.7 +/- 4.4 micrograms/ml; n = 165), but there was no difference between the values in the two groups of thyrotoxicosis patients. The average serum level of calcitonin in destruction-induced thyrotoxicosis patients was 96.7 +/- 66.7 pg/ml (n = 21), which was significantly (P less than 0.05) higher than the values in patients with thyrotoxic Graves' disease (62.0 +/- 44.7 pg/ml; n = 26) and in healthy subjects (63.9 +/- 31.2 pg/ml; n = 29), but the difference in values in the two groups of thyrotoxicosis was not clinically useful because of considerable overlap of individual values. The T3 to T4 ratio is a simple and helpful index for the differentiation of the two types of thyrotoxicosis. A T3 to T4 ratio less than 20 in thyrotoxic patients before therapy is a laboratory signal of destruction-induced thyrotoxicosis or Graves' disease with complications, but final differentiation should be confirmed by measuring radioactive iodine uptake.
Adult↗
Familial euthyroid thyroxine excess: an appropriate response to abnormal thyroxine binding associated with albumin.
Responses of the pituitary-thyroid axis and T4 binding to plasma proteins were studied in three kindreds with familial euthyroid T4 excess, an autosomal dominant condition in which affected subjects have high concentrations of plasma T4 with a high free T4 index, but normal free T4 by equilibrium dialysis. Treatment of affected subjects with exogenous T4 or T3 led to gradual suppression of TSH secretion when the free level of T4 or T3 increased above normal. When total T4 was reduced toward normal by potassium iodide treatment or previous subtotal thyroidectomy, the findings suggested mild hormone deficiency. In affected subjects from all three families, equilibrium dialysis showed increased [125I]T4 binding, with evidence of abnormal high capacity binding when an excess of unlabeled T4 was added. In contrast, T3 binding showed no major abnormality. Serum concentrations of T4-binding globulin, prealbumin, and albumin were normal, but gel electrophoresis and immunoprecipitation of binding proteins indicated that 25-30% of tracer [125I]T4 was albumin bound (normal, 10-12%). Abnormal binding, studied by an adsorption separation system in the presence of T4 excess, was inhibited by increments of barbitone. These findings suggest that T4 excess is an appropriate response to abnormal T4 binding so as to maintain normal free T4. The excess bound T4 is associated with a normal quantity of albumin. The basis for increased T4-albumin binding remains to be determined.
Adolescent↗
Thyroxine metabolism in the low thyroxine state of critical nonthyroidal illnesses.
This study reports in vitro and in vivo parameters of T4 metabolism in patients with critical nonthyroidal illnesses who were selected because of serum total T4 values less than 3 micrograms/dl and normal TSH levels. Despite the depressed total T4 concentrations, the normal serum free T4 values (7 of 9 patients), T4 production rates (8 of 9), and TSH responses to TRH (8 of 8) provided evidence for normal free T4 availability to peripheral tissues. Elevated rT3 values in 10 of 14 patients were consistent with this view. However, serum free T4 index determinations markedly underestimated free T4 (20 of 20). This resulted from failure of the T3 uptake measurement to reflect the defective state of serum T4 binding. Defective serum T4 binding to carrier proteins was evidenced by the 2- to 3-fold increase in both the free fraction and the MCR values for T4. The normal early distribution phase, despite defective serum T4 binding, suggested an additional abnormality of deficient extravascular T4 binding. The blunted TSH response to TRH and the low normal values for both T4 production rates and free T4 levels measured by equilibrium dialysis indicated mild pituitary suppression, possibly related to elevated serum cortisol levels. Since an overt deficiency of free T4 availability does not appear to exist in the low T4 state of critical nonthyroidal illness, T4 therapy cannot currently be recommended.
Acute Disease↗
Dichotomy between serum free triiodothyronine and free thyroxine concentrations in familial thyroxine-binding globulin deficiency.
The mean serum total T4 (3.2 +/- 1.0 micrograms/100 ml) and T3 levels (83 +/- 29 ng/100 ml) in eight euthyroid patients with T4-binding globulin (TBG) deficiency from two families were significantly lower than those in either the unaffected relatives (P less than 0.05) or the control subjects (P less than 0.01). The lowest T4 and T3 values were found in the four hemizygotes (2.4 +/- 0.2 micrograms/100 ml and 69 +/- 25 ng/100 ml, respectively). In contrast to the absolute T4 and T3 levels, the mean percentages of free T4 and free T3 in the affected members were about twice as high as those in either the unaffected relatives or the controls. Despite an elevated percentage of free T4 in each of the TBG-deficient members, the mean absolute free T4 (FT4) level (0.89 +/- 0.20 ng/100 ml) was significantly lower than those in both control groups [1.31 +/- 0.2 ng/100 ml (P less than 0.02) and 1.24 +/- 0.30 ng/100 ml (P less than 0.01), respectively]. Serum FT4 levels were subnormal in three of four hemizygotes. In contrast to FT4, the mean FT3 level in the affected members (0.33 +/- 0.04 ng/100 ml) was significantly higher than that in either the nondeficient relatives (0.25 +/- 0.02 ng/100 ml; P less than 0.02) or the control subjects (0.26 +/- 0.04 ng/100 ml; P less than 0.02), whereas the ratio of FT3 to FT4 was about twice as high. The data suggest that in TBG deficiency, euthyroidism in maintained by a subtle equilibrium between low FT4 and high FT3 levels.
Adolescent↗
Familial euthyroid thyroxine excess: characterization of abnormal intermediate affinity thyroxine binding to albumin.
The abnormal high capacity T4 binding site of familial euthyroid T4 excess was separable from prealbumin and T4-binding globulin but not from albumin. We therefore compared T4 binding by albumin preparations isolated from the sera of normal and affected subjects. By equilibrium dialysis, albumin from affected subjects showed an extra T4 binding site (Kd approximately 50 nM) in addition to the T4 binding sites of normal albumin (Kd approximately 4 microM). Comparison of the estimated capacity of the additional site (200 microM) with the molar concentration of albumin suggested that only about one third of albumin molecules from affected subjects contained the extra binding site. Estimates of affinity and capacity were used to derive combining powers for the diverse classes of serum T4 binding sites. From these estimates, it appears that the presence of the abnormal site accounts for the approximate doubling of normal mean total T4 (from approximately 100 nM or 7.7 micrograms/dl to approximately 200 nM or 15.5 micrograms/dl), in order to maintain a normal free T4 in the face of the increased T4 association with albumin. Studies of [125I]T4 displacement from albumin of affected subjects showed low T3 affinity and competition by barbitone. Relative molar concentrations to give equivalent displacement of [125I]T4 were: 3,3',5,5'-tetraiodothyroacetic acid, 0.4; T4, 1.0; rT3, 4; 8-anilinonaphthalene sulfonic acid, 10; T3, 80; salicylate, 200; and barbitone, 40,000. Studies with dithiothreitol suggested that disulfide bonds were critical in maintaining the T4-albumin association. These findings indicate that familial T4 excess is due to abnormal intermediate affinity, sulfhydryl-sensitive T4 binding sites that are inseparable from the albumin found in affected subjects.
Barbital↗
Slow thyroxine binding globulin in the pathogenesis of increased dialysable fraction of thyroxine in nonthyroidal illnesses.
The expected decreases of serum total T4, total T3, T4 binding prealbumin, and T4 binding globulin (TBG) concentrations were found in a selected series of patients with nonthyroidal illnesses (NTI). An increase in percent dialysable fraction of T4 was also found. Although serum TBG concentrations were decreased, the proportion of a slow moving form of TBG, designated slow TBG (STBG) was increased, the absolute concentration being not significantly different from that measured in controls. Thus the observed decrease in TBG in NTI occurs in the normal TBG fraction which binds T4 much more avidly than does STBG. It is suggested that the increase in the proportion of STBG, due to a decrease in normal TBG, has an important role in the pathogenesis of the increase in percent dialysable fraction of T4 in serum from patients with NTI.
Dialysis↗
A thyroxine-binding protein in human breast milk similar to serum thyroxine-binding globulin.
A thyroid hormone-binding substance (TBGw) similar to serum T4-binding globulin (TBG) has been identified in the whey fraction of human breast milk. TBGw coeluted with serum TBG, as determined by Bio-Gel P-100 chromatography, and has an isoelectric point of 4.2-4.8, similar to that of serum TBG. The affinity constant of TBGw for T4 was similar to that of serum TBG(Ka, 1.54 +/- 0.38 X 10(9) M-1). Marked inhibition of TBGw binding of [125I]T4 was achieved by the addition of 1.5 X 10(-3) M 8-anilino-1-naphthalene-sulfonic acid. An albumin-like low affinity site (Ka, greater than 10(7) M-1) was also found. RIA of whey concentrates serially diluted in TBG-depleted serum indicated nearly identical binding curves for TBGw and TBG, with slopes of 2.33 (n = 15; r = 0.947) and 2.54 (n = 7; r = 0.996), respectively. Using a specific TBG RIA, a TBGw concentration of 0.29 +/- 0.08 microgram/ml (mean +/- SD) in breast milk (n = 26) was determined. Paired serum and whey specimens from individuals between 6 and 20 weeks of lactation were analyzed by TBG RIA; in these individuals, mean serum TBG concentrations were 25.0 +/- 3.4 micrograms/ml (n = 7); corresponding TBGw levels were 0.26 +/- 0.08 micrograms/ml (n = 7), i.e. approximately 1% of serum levels. Nonetheless, linear regression analysis of the data revealed no significant correlation between serum and whey TBG concentrations in these individuals.
Albumins↗
Measurement of thyroxine uptake from serum by cultured human hepatocytes as an index of thyroid status: reduced thyroxine uptake from serum of patients with nonthyroidal illness.
The uptake of T4 from human serum by cultured human hepatoma cells, Hep G2, was compared with the free T4 estimates by equilibrium dialysis (DT4) and a resin uptake method (FT4I). The cellular uptake of T4 (CT4) was highly correlated with DT4 values (r = 0.97; P less than 0.0005) and FT4I values (r = 0.99; P less than 0.0005) in sera from euthyroid subjects and hypothyroid and thyrotoxic patients. In patients with abnormal levels of serum T4-binding globulin, the fractional uptake of T4 decreased as the TBG level increased, and the CT4 value remained within the normal range. Addition of increasing amounts of T4 to serum from a hypothyroid patient did not alter the relationships between CT4 and FT4I and between CT4 and DT4. DT4 and CT4 measurements were compared in sera from 13 patients with severe nonthyroidal illness (NTI). Six samples had DT4 values that clearly overestimated the cellular uptake, 2 patients had DT4 values in the thyrotoxic range but normal CT4 values, and 2 patients had DT4 values in the midnormal range and CT4 values below normal. When FT4I and CT4 values were compared in 19 NTI patients, 5 had FT4I values below the normal range and normal CT4 values. Overall, among patients with NTI, FT4I was low in 11 (58%), normal in 8 (42%), and high in 0; CT4 was low in 6 (32%), normal in 13 (68%), and high in 0, and DT4 was low in 2 (15%), normal in 9 (69%), and high in 2 (15%). In patients with NTI, the results of in vitro estimations of free T4 do not always correlate with the transfer of T4 to tissues, as assessed by T4 uptake in human hepatoma cells. In patients with NTI, equilibrium dialysis may overestimate and resin uptake measurements may underestimate the amount of T4 taken up by tissues. In some patients with severe NTI, tissue uptake of T4 is reduced.
Cell Line↗
Reduced affinity for thyroxine in two of three structural thyroxine-binding prealbumin variants associated with familial amyloidotic polyneuropathy.
T4-binding prealbumin (TBPA), a protein synthesized by the liver, circulates as a tetramer and transports 15-20% of T4. We studied 3 variants of the TBPA monomer recently identified in serum and amyloid fibrils of patients affected by familial amyloidotic polyneuropathy (FAP). They represent single amino acid substitutions at positions 30 (type I), 60 (Appalachian), and 84 (type II). Tests of thyroid function and the apparent association constant (Ka) of T4 binding to TBPA were measured in whole serum from 14 carriers of FAP identified clinically, by amino acid sequence analysis, or by DNA restriction fragment analysis. Significant reduction of Ka was found in subjects with FAP types I and II, but not in subjects with the Appalachian type. Mean (+/- SD) values of 0.24 +/- 0.08 X 10(7) M-1 for type I and 0.26 +/- 0.10 X 10(7) M-1 for type II were significantly (P less than 0.0001) lower than those for normal relatives (1.39 +/- 0.30 X 10(7) M-1) or unrelated normal subjects (1.41 +/- 0.18 X 10(7) M-1). The mean Ka value for the five subjects with FAP of the Appalachian type was slightly but not significantly reduced (1.08 +/- 0.11 X 10(7) M-1). There was no overlap of individual Ka values of subjects with types I and II TBPA with those of subjects from all other groups. Abnormalities of thyroid function included slight but significant reductions of the mean total serum T4 concentration in the subjects with type II FAP and the mean serum total T3 concentration in those with type I FAP. Four subjects with FAP (two type II and two of the Appalachian type) had biochemical evidence of hypothyroidism. The three subjects with total serum T3 levels below the limit of normal had amyloid cardiomyopathy. These results indicate that TBPAs from subjects with FAP types I and II have relatively lower affinity for T4. Although none of the substituted amino acids in these variant TBPAs contribute directly to the surface of the putative T4-binding site, the side chains of amino acids 30 and 84, but not 60, interact with internal residues of the beta-structure which forms the presumed binding site, in agreement with our results of Ka measurements. The high incidence of hypothyroidism is due to the probably fortuitous occurrence of Hashimoto's thyroiditis as well as to partial destruction of the thyroid gland by amyloid deposits.
Amyloidosis↗
Normal cellular uptake of thyroxine from serum of patients with familial dysalbuminemic hyperthyroxinemia or elevated thyroxine-binding globulin.
To determine whether thyroid hormone-binding proteins in serum, particularly albumin, facilitate the transfer of T4 into human tissues, we studied cellular T4 uptake (CT4) by human liver (Hep G2) cells from medium containing serum from subjects with familial dysalbuminemic hyperthyroxinemia (FDH) and acquired and familial T4-binding globulin (TBG) excess and patients with normal T4-binding to albumin and normal TBG concentrations. Serum from nine subjects with FDH whose mean serum total T4 (TT4) concentration was 203 +/- 27 nmol/L were matched for TT4 concentrations with serum from nine subjects with acquired TBG excess (TT4, 201 +/- 23 nmol/L) and nine subjects with thyrotoxicosis and normal TBG concentrations (TT4, 205 +/- 28 nmol/L). The subjects' CT4 results were compared to their serum free T4 concentration, measured by equilibrium dialysis (DT4), and their serum free T4 index (FT4I) value. The mean serum DT4 value for the subjects with FDH (23 +/- 5 fmol/L) and those with TBG excess (23 +/- 3 fmol/L) were normal, whereas it was elevated (44 +/- 9 fmol/L; P less than 0.001) for the thyrotoxic patients with normal TBG concentrations. The mean CT4 value also was normal for the subjects with FDH (37.7 +/- 4.9 fmol/plate) and those with TBG excess (36.6 +/- 4.6 fmol/plate), but was elevated for the thyrotoxic patients (62.3 +/- 11.2 fmol/plate; P less than 0.001). In all three groups studied, the relationship between individual CT4 and DT4 values was similar to that previously found in subjects with no T4-binding protein abnormalities. The mean serum FT4I value was lower for the subjects with acquired TBG excess (111 +/- 22) than for the subjects with FDH (133 +/- 22; P less than 0.05), and it was much higher for the subjects with thyrotoxicosis (221 +/- 31; P less than 0.001). In the subjects with FDH and those with thyrotoxicosis the normal relationship between CT4 and FT4I was maintained, while in the subjects with acquired TBG excess, FT4I values were lower than expected. In seven of the nine subjects with TBG excess, the abnormality was associated with conditions known to increase its sialic acid content: hepatitis (one subject), pregnancy (four subjects), and estrogen therapy (two subjects). The CT4 values were similar in nine subjects with acquired TBG excess (seven pregnant women and two subjects with chronic active hepatitis) and five subjects with familial TBG excess (34.8 +/- 4.3 vs. 34.0 +/- 8.6 fmol/plate, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)
Cell Line↗
A new inherited abnormality of thyroxine-binding globulin (TBG-San Diego) with decreased affinity for thyroxine and triiodothyronine.
Evaluation of a family in which males were clinically euthyroid despite having low serum total T4 (TT4) and free T4 index (FT4I) values revealed the presence of a new inherited T4-binding globulin (TBG) variant (TBG-San Diego). Two brothers had low TT4 (39 and 49 nmol/L; normal range, 64-154 nmol/L) and FT4I (4.0 and 4.4; normal range, 6.0-10.5) values, while their grandfather, despite treatment with T4, had a low TT4 (53 nmol/L) and normal FT4I (7.2) in the presence of suppressed TSH (less than 0.1 mU/L). When measured by RIA, the mean TBG concentration (TBG-RIA) of the three affected males was low normal [160 +/- 56 (+/- SD) nmol/L; normal range, 151-253]. Their TBG-binding capacity measured by a T4 binding assay at saturation (TBG-CAP) was similar, giving a mean TBG-RIA/TBG-CAP ratio not significantly different from 1.0. In these males, the TBG affinity for T4 (Ka = 0.48 +/- 0.04 x 10(10) mol-1) was less than that in subjects with the common type TBG (TBG-C; Ka = 1.10 +/- 0.14 x 10(10) mol-1; P less than 0.0001) and similar to that in Aboriginal males from Australia with the variant TBG-A (0.52 +/- 0.10 x 10(10) mol-1). TBG affinity for T3 in the affected males (Ka = 0.68 +/- 0.05 x 10(9) mol-1) was less than that in subjects with TBG-C (1.39 +/- 0.12 x 10(9) mol-1; P less than 0.00001), but greater than that in males with TBG-A (0.44 +/- 0.03 x 10(9) mol-1; P less than 0.0005). The rate of TBG denaturation at 56 C was increased in the affected males (t1/2 = 28.4 and 26.9 min) compared to that in subjects with TBG-C (t1/2 = 54.1 +/- 7.1 min), but was lower than that in males with TBG-A (t1/2 = 20.8 +/- 1.9). A value intermediate between those in affected males and normal subjects was found in serum from an obligatory heterozygote. Microheterogeneity on isoelectric focusing was normal. The exact nature of this structural TBG variant is not yet known. The presence of a TBG mutant should be considered in healthy, clinically euthyroid patients with low serum TT4 and free T4 index values, especially when such low values are found in several members of the same family.
Adult↗
Drug competition for thyroxine binding to transthyretin (prealbumin): comparison with effects on thyroxine-binding globulin.
We examined the effect of 26 drugs on T4 binding to transthyretin (TTR; prealbumin) and T4-binding globulin (TBG) by determining their ability to inhibit [125I]T4 binding to TTR isolated from normal human plasma and to serum diluted 1:10,000, respectively. The hierarchies for drug inhibition of T4 binding differed greatly for these two proteins. Relative to T4, the drugs were much more potent inhibitors of [125I]T4 binding to TTR than to TBG. Compounds of the anthranilic acid class, such as flufenamic, meclofenamic, and mefenamic acids, interacted particularly strongly with TTR. Flufenamic acid was more potent than T4 itself in inhibiting [125I]T4 binding [175 +/- 17% (+/- SD); cf. T4; n = 3; P less than 0.001], while mefenamic acid, diflunisal, and meclofenamic acid were 20-26% as potent as T4 in their interaction with TTR. The reactivity of diclofenac, fenclofenac, indomethacin, sulindac, and the diuretic ethacrynic acid was 0.8-2.1% relative to that of T4. In contrast, furosemide, the drug most highly reactive with TBG, was only 0.11 +/- 0.03% (n = 7) as potent as T4, followed by meclofenamic acid greater than mefenamic acid greater than fenclofenac greater than flufenamic acid greater than diflunisal greater than milrinone. Aspirin and sodium salicylate were, respectively, 0.05% and 0.20% as active as unlabeled T4 as inhibitors of [125I]T4 binding to TTR, but these compounds had only 3-4 x 10(-6)% of the activity of T4 for TBG binding. Diphenylhydantoin had no detectable effect on T4 binding to TTR and was 2.9 x 10(-4)% as reactive as T4 with TBG. Amiodarone did not interact with either binding site. Drug interactions with TTR may be important when this protein becomes a major circulating T4-binding protein, as in patients with complete or partial TBG deficiency, or when serum T4 is markedly elevated. Such interactions may also be important where TTR is the dominant tissue T4-binding protein, as in the choroid plexus. In addition, the drug competitors described here may be useful as probes to further define the structural basis for specific ligand interactions with different classes of T4-binding sites.
Binding Sites↗
[Effect of ee fatty acids (FFA) on free thyroxine fraction (FT4F) (effects on thyroxine-binding protein)].
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Barbiturates↗
[Metabolism of triiodothyronine and thyroxine in a case of thyroxine binding globulin deficiency with hypothyroidism].
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Adult↗
[Total and free serum thyroxine and triiodothyronine levels and the effect of estrogen in a family with thyroxine-binding globulin deficiency].
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Adolescent↗
[The association constant of thyroxine binding globulin for thyroxine in patients with hyperthyroidism (author's transl)].
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Humans↗
An attempt to compare the affinity of thyroxine-binding-globulin to thyroxine in normal and hyperthyroid sera.
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Adult↗