Free Thyroid Hormone Concentrations Research Articles

Inositol and hepatic lipidosis. II. Effect of inositol supplementation and time from parturition on serum insulin, thyroxine and triiodothyronine and their relationship to serum and liver lipids in dairy cows.

Percutaneous liver biopsies and blood samples were obtained from 80 dairy cows in nine Michigan herds over the peripartum period. Thirty-nine cows were fed 17 g of supplemental inositol and 41 were fed a placebo. Liver biopsies were assayed for total myoinositol and triglyceride (TG) concentrations. Blood samples were assayed for serum dextran precipitable cholesterol, nonesterified fatty acids (NEFA), insulin, thyroxine (T4), free (FT4), triiodothyronine (T3) and free T3 (FT3) concentrations. Serum concentrations of insulin and the thyroid hormones decreased near parturition, with lowest concentrations occurring in the immediate postpartum period. Concentrations of T3 correlated well with T4, and the concentrations of free thyroid hormones reflected concentrations of total thyroid hormones. The percentage of hormone in the free fraction remained constant over time. Serum insulin, T3 and T4 were negatively correlated with serum NEFA and liver TG concentrations. Thyroid hormone concentrations were positively correlated with serum dextran precipitable cholesterol concentrations. Inositol supplementation was associated with reduced circulating T3 and FT3 concentrations, but not T4 and FT4 concentrations. Changes in hormone concentrations at parturition and their relationship to liver TG and serum NEFA concentrations were consistent with a metabolic adaptation by the dairy cow to the negative energy balance of early lactation.

Estimation of free thyroid hormone concentrations in the clinical laboratory.

A multiplicity of tests have come into routine use for the estimation of the concentrations of free thyroid hormones in serum and plasma since the introduction, almost three decades ago, of the hypothesis that only the free thyroid hormone is metabolically active. Most of these tests give estimates of considerable diagnostic value, although results may be unreliable in some clinical situations. This review outlines the methods currently available for estimating free thyroid hormones and highlights the extrathyroidal and physiological factors influencing the results of such tests, particularly for the analog-based techniques.

Binding characteristics of thyroxin binding globulin in serum of normal, pregnant, and severely ill euthyroid patients.

Serum from normal, pregnant, and severely ill patients was stripped of endogenous thyroid hormones and diluted 1100-fold in barbital buffer. We then used it to study the binding characteristics of thyroxin binding globulin (TBG), noting significant differences in binding capacities among the groups. The mean (+/- SD) triiodothyronine/thyroxin ratio for binding capacity was 18 +/- 4 for normal subjects. The ratio was significantly increased in pregnant patients, 21 +/- 4 (p less than 0.05), and significantly lower in severely ill patients, 12 +/- 4 (p less than 0.05). When serum was diluted before assay, to give a uniform TBG concentration among groups, these apparent differences in binding characteristics were eliminated. It therefore is unlikely that different molecular species of TBG account for the variations in binding characteristics in these clinical states. Apparently, the distribution of thyroxin and triiodothyronine among the binding sites on TBG changes with variations in TBG concentration. This may explain the discrepancies observed in the concentrations of free thyroid hormones as estimated by various methodologies.

Free thyroxin and free triiodothyronine as measured by equilibrium dialysis and analog radioimmunoassay in serum of patients taking phenytoin and carbamazepine.

We measured free thyroxin (FT4) and free triiodothyronine (FT3) in serum of patients taking the anti-epileptic drugs phenytoin and carbamazepine, both by equilibrium dialysis procedures and analog-type radioimmunoassays. By either assay, the mean concentration of FT4 was significantly decreased in patients receiving either drug, whereas their FT3 concentrations were normal or only slightly decreased. Adding therapeutic concentrations of these drugs in vitro to control sera had a small or no incremental effect on FT4 and FT3 as measured by either method, but adding greater concentrations of the drugs in vitro markedly increased the concentrations of the free hormones. These results indicate that the main mechanism of the decrease in concentrations of free thyroid hormones in serum during therapy with anticonvulsant drugs is not the displacement of hormones from their binding to plasma proteins. We also determined, using a new and sensitive immunoradiometric assay, that patients taking carbamazepine, but not those taking phenytoin, had significantly less thyrotropin in the serum.

The effect of propranolol on circulating thyroid hormone measurements in thyrotoxic and euthyroid subjects.

Circulating concentrations of total and free thyroid hormones and thyroid hormone binding proteins were measured in thyrotoxic and euthyroid subjects treated with propranolol. In the thyrotoxic group, total triiodothyronine (T3) concentration fell after propranolol therapy, suggesting an effect of the drug on the peripheral conversion of thyroxine (T4) to T3. In euthyroid subjects, a rise in circulating concentrations of free T4 and reverse T3 (rT3) was observed, while only a small decrease in free T3 was evident. Thyroxine binding globulin (TBG) concentration fell during propranolol treatment while thyroxine binding prealbumin (TBPA) concentration rose. The changes observed in the euthyroid state are consistent with inhibition of peripheral deiodination of T4 and rT3; an additional effect of propranolol on binding protein metabolism was evident.

Phenytoin and thyroid hormone action.

Circulating free thyroid hormone concentrations are reduced in subjects taking long-term phenytoin, a finding at variance with their euthyroid clinical state and normal serum TSH concentration. It is suggested, therefore, that phenytoin may modify the cellular effects of thyroid hormones. In order to examine the influence of phenytoin on thyroid hormone action in the pituitary gland we studied its effect on the binding of tri-iodothyronine (T3) to isolated nuclei prepared from rat anterior pituitary tissue. Phenytoin inhibited the nuclear binding of T3 in a dose-dependent fashion. Phenytoin also partially inhibited thyrotrophin-releasing hormone-stimulated TSH release from cultured rat anterior pituitary cells. These studies provide evidence for a direct effect of phenytoin on the thyrotroph mediated via nuclear T3 receptor binding.

Thyroid dysfunction in patients on regular hemodialysis: evaluation of the stable intrathyroidal iodine pool, incidence of goiter and free thyroid hormone concentration.

Thyroid function tests and stable intrathyroidal iodine were evaluated in 17 patients on regular hemodialysis treatment (RHD). Triiodothyronine levels in the hypothyroid range, thyroxine levels in the low normal range, but normal levels of thyroid-stimulating hormone, free thyroxine and free triiodothyronine were found. Normal values of stable intrathyroidal iodine and a normal incidence of goiter for our region were also found. It is concluded that in patients on RHD: (1) free thyroid hormone levels are normal and probably represent the most meaningful way of evaluating thyroid function; (2) in our RHD population goiter is no more prevalent than in normal persons; (3) the iodine storage function of the thyroid is not always altered.

Total and free thyroid hormone concentrations in patients receiving replacement treatment with thyroxine

Total and free thyroid hormone concentrations in patients receiving replacement treatment with thyroxine

Total and free thyroid hormone concentrations in patients receiving replacement treatment with thyroxine.

Total and free thyroid hormone concentrations in patients receiving replacement treatment with thyroxine.

Theoretical consideration of the effects of dilution on estimates of free thyroid hormones in serum.

When concentrations of free thyroid hormones in serum are measured by equilibrium dialysis, the serum sample is diluted by dialysis buffer, resulting in a new equilibrium for distribution of these hormones that differs from that in the original serum sample. We have derived a mathematical formulation, based on an equilibrium model for multiple ligands and multiple binding sites, to determine the effect of dilution on the concentrations of free hormones in serum. Computer simulations based on the formulation indicate that both free thyroxin (T4) and free triiodothyronine (T3) are decreased by dilution of serum, free T3 being affected more than free T4. This dilution-related decrease is more prominent in hyperthyroidism than in euthyroidism, and even more striking for sera in which binding capacities for thyroid hormones are decreased (e.g., in thyroxin-binding globulin deficiency or hypoalbuminemia). These simulations can provide a basis for minimizing experimental errors in the estimates of concentrations of free thyroid hormones by equilibrium dialysis.

Total and free thyroid hormone concentrations in patients receiving maintenance replacement treatment with thyroxine.

Total and free serum concentrations of thyroxine and triiodothyronine were measured in 122 subjects with hypothyroidism who were clinically well while receiving conventional replacement treatment with thyroxine. In a third of patients concentrations of total and free thyroxine were raised, often considerably; nevertheless concentrations of total and free triiodothyronine were usually normal. Though significant correlations were obtained between total triiodothyronine concentrations and total thyroxine concentrations (p less than 0.001) and between the triiodothyronine concentrations and free thyroxine concentrations (p less than 0.001) the slope of the line of the regression equation describing these correlations was small, hence large increases in both total and free thyroxine concentrations were accompanied by only modest increases in total and free triiodothyronine concentrations. The presence of total or free thyroxine concentrations above normal in patients taking thyroxine therefore are not necessarily of clinical consequence. In the assessment of adequacy of replacement treatment with thyroxine the most logical combination of in vitro thyroid function test results may be a normal thyrotrophin concentration and normal free triiodothyronine concentration.

The role of serum binding proteins in determining free thyroid hormone concentrations during development in quail.

Japanese quail were used as a model for studying the role of binding proteins in determining free T4 (FT4) and free T3 (FT3) concentrations during development. Adults were used to characterize thyroid hormone binding; developmental stages studied were late embryonic, perinatal, hatchling, and juvenile. Total and free hormones were determined directly by RIA, and free hormones were determined indirectly by equilibrium dialysis. Binding proteins were identified by electrophoresis of serum preincubated with labeled hormones. Serum FT4 and FT3 concentrations in adult quail were equivalent to those in humans. T4 bound principally to albumin and secondarily to prealbumin; T3 bound principally to alpha-globulin and secondarily to albumin and gamma-globulin. A specific T4-binding globulin, as in mammals, was not present. The relative affinity of stripped serum was greater for T4 than for T3. In late embryos, FT4 concentrations rise as a result of a marked increase in total T4 (TT4) and modest increases in binding proteins. The perinatal peak in FT4 reflects the perinatal surge of TT4 without a change in binding proteins. From days 1-6 posthatching, FT4 decreases as a consequence of TT4 decreasing faster than the decrease in binding. In juveniles, FT4 concentrations stabilize as increases in TT4 are paralleled by increases in serum binding. T3 binding shows few significant differences from adult values during development, so FT3 concentrations follow closely the pattern of TT3 changes. These results demonstrate that developmental changes in serum binding proteins play a significant role in determining the pattern of free thyroid hormones, especially for FT4, by modulating the total hormone concentrations controlled by the hypothalamic-pituitary axis.

Serum free thyroid hormones in T3-toxicosis: a study of 35 patients.

Few data are available on serum free thyroid hormone concentration in patients with T3-toxicosis. In this study total and free T4 and T3 and TBG were evaluated in 35 subjects with T3-toxicosis, including 12 with untreated Graves' disease, 5 Graves' patients on methimazole treatment, 13 with autonomous adenoma, 3 with multinodular goiter, and 2 with subacute thyroiditis. T4, T3, free T4 (FT4), free T3 (FT3) as well as calculated T4/TBG and T3/TBG ratios were significantly higher in patients than in 37 healthy controls. Serum FT4 levels above the normal range were found in 19 subjects with T3-toxicosis (9 with untreated and one with methimazole-treated Graves' disease, 6 with autonomous adenoma, 1 with multinodular goiter and 2 with subacute thyroiditis). These data, together with the few previous reports, indicate that high FT4 levels are present in about half of the patients with so called T3-toxicosis, and that this occurs more frequently in diffuse than nodular goiter. It is suggested that the term T3-toxicosis be used only for those subjects with normal total and free T4.

Rapid adaptation of pituitary responsiveness to TRH in the post-surgical state. The role of free T3.

In eight clinically and biochemically euthyroid patients undergoing routine major non-thyroidal surgery preoperative and daily postoperative serum concentrations of total and free thyroid hormones were measured. Thyrotrophin-releasing hormone (TRH) tests were performed preoperatively and on the first 3 postoperative days. There was a significant fall in mean serum total and free triiodothyronine (T3) concentrations on the postoperative days and mean reverse T3 concentrations rose reciprocally. There was no significant change in mean basal thyroid-stimulating hormone (TSH) values, but there was a significant increase in the mean TSH-response to TRH on the first postoperative day. The mean TSH response than declined sequentially until day 3 while mean free T3 concentrations remained significantly depressed. Mean serum free thyroxine(T4)concentrations remained normal during the study. Intrapituitary conversion of T4 to T3 or other down regulatory mechanisms could explain this rapid adaptation of the pituitary axis.

Variable thyrotropin response to thyrotropin-releasing hormone after small decreases in plasma free thyroid hormone concentrations in patients with nonthyroidal diseases.

Although a normal serum thyrotropin (TSH) concentration is generally considered to be the most important finding to support the clinical impression of euthyroidism in patients with nonthyroidal diseases and decreased serum triiodothyronine (T(3)), the regulation of TSH secretion in sick patients has not been studied previously. Accordingly, we studied the regulation of TSH secretion in 23 patients with nonthyroidal diseases; 15 of the patients had decreased serum T(3). TSH regulation was studied by measuring the TSH response to injected thyrotropin-releasing hormone (TRH) before and after effecting a small decrease in serum thyroxine (T(4)) and/or T(3) concentrations by iodide treatment, 262 mg daily for 10 d. Iodide treatment significantly decreased (> 10%) the free T(4) index (FT(4)-I) and/or free T(3) index (FT(3)-I) in all patients. FT(4)-I values were correlated (0.611, P < 0.001), with free T(4) concentration determined by equilibrium dialysis. Despite decreased FT(4)-I and/or FT(3)-I after iodide treatment in all patients, the TSH response to TRH after iodide treatment was augmented in only 8 of 15 patients who had decreased serum T(3) (group 1) and in only 5 of 8 patients who had a normal serum T(3). Mean base-line TSH concentration was increased significantly (P < 0.05) from 0.9+/-0.1 to 1.5+/-0.3 muU/ml in group 1 only. Comparison of the mean TSH response to TRH showed that there was no significant difference between groups 1 and 2. Moreover, no significant difference in thyroidal parameters was observed between patients who had augmented TSH response to TRH after iodides and those who had either similar or decreased TSH response irrespective of the initial serum T(3). These studies show that an augmented TSH response to TRH in response to a small reduction in serum T(4) and T(3) concentration occurred in only 57% of the entire group of patients with nonthyroidal diseases and that the presence or absence of a normal TSH response to this stimulus did not seem to be related to the base-line serum T(3) concentration. Because an increase in serum TSH in response to decreased serum T(4) and T(3) did not occur in about one-half of patients with nonthyroidal diseases, normal serum TSH may not be a reliable index of the euthyroid state in these patients.

Thyroid function in thalassaemia major.

Serum concentrations of T4, T3, rT3, and TSH were measured by radioimmunoassay in 45 patients suffering from beta-thalassaemia. A TRH stimulation test was performed and the binding capacity of TBG and TBPA for T3 and T4 measured by reverse flow zone electrophoresis in a group of these patients. Mean T4 serum concentration was lower in thalassaemic patients than controls; T3, rT3, TSH levels, and the pituitary response to TRH were normal. TBPA binding capacity for thyroxine was greatly decreased, probably due to iron overload impairing the liver function. The decreased circulating total thyroxine might be explained by the reduced TBPA capacity, serum free thyroid hormone concentration total thyroxine might be explained by the reduced TBPA capacity, serum free thyroid hormone concentration values being normal. It is concluded that thalassaemic children are euthyroid, despite often having low-normal or subnormal thyroxine levels.

Free thyroid hormone concentrations during postnatal development in the rat.

Sprague-Dawley rats were sacrificed by decapitation at 5, 7, 12, 14, 22, 26, 32, and 40 days of age. Adult animals (175 to 225 g) were also studied. Serum-free thyroxine (FT4) concentrations rose rapidly between 5 and 12 days to levels similar to adult concentrations, whereas the percentage of FT4 was relatively high between 5 and 12 days before declining to adult values by 14 days. Serum-free triiodothyronine (FT3) concentrations rose progressively to attain peak concentrations at 26 days and subsequently declined to adult levels by 40 days. The percentage FT3 rose in parallel with the FT3 concentrations to peak values at 22 to 26 days before declining to adult levels. FT4/thyroid-stimulating hormone (TSH) and FT3/THS ratios increased progressively through 22 days of age in parallel with the FT3/FT4 ratio. These data indicate that free thryoid hormone concentrations follow essentially the same developmental profile as do total thyroid hormone concentrations. Progressive maturation of the negative feedback control mechanism for the pituitary-thyroid axis, as assessed by the FT4/TSH and FT3/TSH ratios, occurs through 14 days. However, the continued rise in FT3 concentrations, FT3/TSH, and FT3/FT4 ratios through 26 days suggests a further resetting of the setpoint of the pituitary-thyroid axis possibly related to the stress of weaning.

Free thyroxine (FT4) and free triiodothyronine (FT3) in autonomous thyroid nodules.

Total and free thyroid hormones (T3, T4, FT3 and FT4), TSH and its response to TRH were determined in sixty-three patients affected by autonomous thyroid nodules: mean concentrations of free T3 (FT3) were significantly higher in hot nodules (suppressing extranodular tissue on the scan) as compared to warm ones, even in those cases where total T3 and T4 were within normal ranges (hot nodules, group as a whole: 8.8 +/- 3.5 pg/ml; warm nodules: 5.3 +/- 1.2; hot nodules with normal total T3 and T4 concentrations: 7.5 +/- 3). Also the clinical condition of thyrotoxicosis appeared to be correlated with FT3 concentrations (toxic patients, group as a whole: 9.6 +/- 4.0 pg/ml; euthyroid patients: 6.8 +/- 3.1; toxic patients with normal values of T3 and T4; 8.3 +/- 2.8). On the contrary the correlation of total and free thyroid hormone concentrations with the response of TSH to TRH was not significant.

Total and free thyroid hormone concentrations after elective surgery.

Changes in thyroid hormone concentration and distribution and plasma cortisol levels have been followed in 11 patients undergoing elective cholocystectomy. A significant rise in total and free thyroxine (T4) and fall in total and free triiodothyronine (T3) were noted after surgery. Reverse T3 concentrations rose substantially, suggesting that peripheral conversion of T4 to T3 is diminished and that there is preferential formation of reverse T3. Serum thyroid stimulating hormone concentrations did not change. There was no direct correlation between the change in cortisol and the change in thyroid hormone or reverse T3 concentrations.

Free T4, free T3 and free reverse T3 in dialysates of serum. The influence of electrolytes and pH with special reference to the physiological range.

The influence of electrolyte composition and pH of buffer on free T4, free rT3, and free T3 concentrations in serum dialysates has been evaluated, using an equilibrium dialysis method with subsequent direct radioimmunoassay estimations of the dialysate. Cl-, HCO3- and H+ were found to be the important ions which at concentrations similar to those occurring in vivo decreased the protein binding of all three hormones in serum, T3 being much less sensitive to these changes than T4 and rT3. The possible influence of pathological concentrations of electrolytes in serum on estimated free thyroid hormone concentrations is discussed. Because the effect of in vivo changes in serum Cl-, HCO3- and H+ on free thyroid hormone concentrations to a certain extent tend to counteract each other, it is concluded that electrolyte and pH disturbances only to a minor extent can affect measurements on free T4, free rT3 and free T3 concentrations in serum obtained by an equilibrium dialysis method.