Serum FT4 Concentrations Research Articles

Dissociated thyromimetic effects of 3, 5, 3'-triiodothyroacetic acid (TRIAC) at the pituitary and peripheral tissue levels.

Although TRIAC is bound at least twice as avidly to nuclear receptor as T3, its thyromimetic potency is relatively low and its effect at the pituitary level on thyrotropin (TSH) secretion seems to be dissociated from that at the peripheral tissue level. In order to gain further insight into the complex effects of this thyroid hormone analog, we studied the effects of long-term TRIAC administration (2.8 mg/day for 2 months) on TSH secretion, circulating free thyroid hormone (FT4 and FT3) levels and some parameters able to evaluate the peripheral thyroid hormone action, in 5 mild obese subjects on low caloric diet (1200 kcal/day). The results were compared to those obtained in 5 mild obese subjects matched for age, sex and weight on low caloric diet alone. TRIAC administration completely inhibited the secretion of both basal and TRH-stimulated TSH in few days, and consequently serum FT4 and FT3 concentrations progressively dropped to very low levels, while no significant changes in both TSH and free thyroid hormone levels were recorded in the control group. The body weight significantly fell in both groups, without any difference between TRIAC treated and untreated patients. The heart rate was constant throughout the course of the study in both groups of patients. Serum total cholesterol, triglyceride and total lipid concentrations significantly decreased in both groups, and the decrement recorded in TRIAC treated patients was not significantly different from that found in patients on diet alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Concentrations of iodothyronines in serum of patients with chronic renal failure and other nonthyroidal illnesses: role of free fatty acids.

The mean concentration of free thyroxin (FT4) in serum, as determined by direct equilibrium dialysis, was decreased in patients with chronic renal failure (CRF) and increased in patients with various other nonthyroidal illnesses (NTI). The mean concentration of dialyzable free triiodothyronine (FT3) in serum was equally low in both groups of patients. Patients with CRF of various etiology but a similar degree of renal failure as estimated from serum creatinine assay had very similar concentrations of FT4 and FT3 in their serum. Mean thyroxin (T4) and triiodothyronine (T3) concentrations in serum were decreased in CRF and NTI, whereas the mean reverse-T3 concentration in serum was normal in CRF and increased in NTI. T4-binding globulin and albumin were markedly decreased in CRF and NTI; T4-binding prealbumin was increased in CRF and decreased in NTI. The mean concentration of nonesterified free fatty acids (FFA) in serum was increased in NTI but not in CRF. The weak, but significant, positive correlation observed between FT4 and FFA in serum (r = 0.34, P less than 0.01) in NTI indicates that the increase in serum FT4 in this group of patients could be an effect, at least in part, of FFA competing with T4 for binding sites on serum proteins. The stronger correlation detected between the serum FT4 concentration and the FFA/albumin molar ratio in serum (r = 0.60, P less than 0.001) demonstrates the importance of a low albumin concentration for expression of the effect of FFA on FT4 in severe systemic illnesses.

Effects of Age and Health on the Euthyroid Reference Ranges for Serum Free Thyroxine and Free Triiodothyronine

Age-related trends in serum free thyroxine (FT4) and free triiodothyronine (FT3) concentrations were measured in 7248 euthyroid subjects (age-range 3 months to 106 years). 5700 were patients referred to hospitals for investigation of suspected thyroid dysfunction, but who were diagnosed euthyroid. 1548 were healthy blood donors (age-range 18-63 years) with no indication of thyroid dysfunction. FT4 concentrations were little affected by the age, the sex or the state of health of the subjects in either group. Serum FT3 concentrations were significantly affected by both age and health factors. The upper limit of the euthyroid reference range for young subjects up to 15 years was about 20% higher (10.4 pmol/l) than for adult subjects older than 25 years (8.8 pmol/l). The change in the upper limits typical of young subjects to that typical of adults occurred steadily over the decade 15-25 years. After this age, little further change occurred, especially in healthy subjects. Additionally, the lower limit of the euthyroid range for FT3 was extended by the inclusion in the reference group of patients referred to hospitals. Compared with the lower limit of the FT3 range for healthy subjects (5 pmol/l), the corresponding limit for referred subjects (young or adult) was 3.5-3.8 pmol/l. Broadening of the FT3 reference range was probably brought about by a significant number of patients in the hospital-referred group with the "low-T3 syndrome" of mild non-thyroidal illness. Accordingly, FT3 was inferior to FT4 in the discrimination of hypothyroidism, as FT4 was unaffected by this phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal models of nonthyroidal disease.

Rats bearing transplantable Walker 256 carcinoma provide an opportunity to assess thyroid function and activity during an interval of time when the tumor has not affected growth rate. Rats with tumor have decreased serum T4 and T3 concentration and decreased serum FT4 and FT3 as well. These changes are due to a decrease in binding of iodothyronines by the serum binding proteins, an increase in the fractional rate of T4 metabolism and a decrease in thyroidal secretion. The decrease in activity of the thyroid gland appears to be due to reduced sensitivity of the thyroid to circulating TSH. Despite decreased serum FT4 and FT3 concentrations, serum TSH remains normal, not increased as would be anticipated in a hypothyroidal animal. Nevertheless, a further experimental decrease in serum T4 and/ or T3 from the already reduced serum iodothyronine levels of the tumor bearing rat results in a normal increment in serum TSH. Thus, TSH secretion appears to be regulated normally despite decreased concentrations of pituitary nuclear T3. This finding suggests that tumor bearing rats have greater than normal sensitivity to T3 in their regulation of TSH secretion. Rats with Walker 256 carcinoma have decreased concentrations of hepatic nuclear T3 receptors and a decrease in T3 specifically bound to the receptors. The fractional occupancy of hepatic nuclear receptors appears relatively normal. The dose-response of alpha-GPD in relation to fractional nuclear T3 receptor occupancy appears shifted up and to the left in tumor bearing rats, whereas the curve for ME is shifted down to the right. The appearance rates of these enzymes are described by similar functions. These findings suggest that postreceptor factors in tumor bearing rats may result in augmentation of some and depression of other biologic responses to thyroid hormones. If the results of these studies are extended to sick patients, they may provide a possible mechanism whereby patients maintain the euthyroid clinical state despite a decrease in serum T3. Thus, postreceptor factors may enhance those thyroidal responses which characterize the euthyroid clinical state. Moreover, attenuation of other thyroidal responses related to conservation of protein may provide a distinct adaptive advantage to the patient with nonthyroidal illness with or without decreased food consumption.

IN VITRO EFFECTS OF HEPARIN ADMINISTRATION ON FREE THYROXINE CONCENTRATIONS

We have demonstrated previously that heparin produces an increase in serum free thyroxine (FT4) measured by 2 step radio-immunoassay or equilibrium dialysis in some patients. The mechanism by which heparin administration acts to increase serum concentrations of FT4 was investigated in 12 patients. Blood was collected from each patient before and after an intravenous dose of heparin. Each sample was divided into 2 portions. Paraoxon, an inhibitor of lipase activity, was added to 1 portion. FT4 and non-esterified fatty acids were analyzed. FT4 was 1.4±0.2 (Mean±SD) and 1.4±0.3 ng/dl in the samples before heparin administration with and without paraoxon, respectively. After heparin administration, FT4 was 1.8±0.7 ng/dl in the samples not containing paraoxon (p < 0.01) and 1.5±0.2 ng/dl in the samples containing paraoxon (NS). Non-esterlfied fatty acid concentrations increased 10 fold on the average after heparin administration in the samples without paraoxon (p < 0.01). In the samples containing paraoxon, there was no Increase in non-esterified fatty acid concentrations after heparin administration. There was significant correlation between FT4 and non-esterified fatty acid concentrations (r = 0.93, p <0.01) In serum after heparin administration which did not contain paraoxon. There was a significant correlation between plasma triglyceride concentrations and non-esterified fatty acid concentrations after heparin administration in the samples not containing paraoxon. The effect of heparin administration on non-esterified fatty acids occurs primarily in vitro after blood withdrawal by continued hydrolysis of plasma triglycerides. The resultant elevated non-esterified fatty acids in turn appear to displace thyroxine from its binding sites on plasma proteins. Caution should be exercised in the interpretation of FT4 after administration of heparin.

Amiodarone kinetics after single i.v. bolus and multiple dosing in healthy volunteers.

We studied three healthy volunteers after a single i.v. bolus of amiodarone, during 1 month of chronic oral dosing and after the discontinuation of the drug. Blood concentrations of amiodarone declined rapidly in a bi-exponential fashion after i.v. bolus. The terminal half-life ranged from 10 to 17 h; after discontinuation of chronic treatment the terminal half-lives were 8-21 days. The i.v. data, the trough levels during multiple dosing and the washout phase could be simultaneously fitted using a triexponential equation. The subjects were carefully monitored for cardiac and thyroid function. One subject had to stop taking amiodarone because of profound bradycardia. A reduction of serum TT3 and FT3 concentrations and an increase of serum rT3 and FT4 was found.

Circulating free T3 in pregnancy, liver diseases, diabetes mellitus and thyroid diseases

Measurement of serum concentrations of free triiodothyronine (FT3) is considered to be an accurate index of thyroid function in the patient. In this study, we measured serum concentrations of FT3, free thyroxine (FT4) and reverse triiodothyronine (rT3) by radioimmunoassay in blood samples taken from the navel cord of 20 newborns as well as 20 nonpregnant women, 20 pregnant women, 10 patients with liver diseases, 25 patients with diabetes mellitus, 65 patients with hyperthyroidism, 30 patients with primary hypothyroidism and 29 normal subjects. In pregnant women, serum FT3 and FT4 levels gradually decreased as the pregnancy progressed. In cord blood, FT3 levels were less than a quarter of the values found during the first trimester of pregnancy or that of non-pregnant women, whereas serum rT3 levels were drastically increased. In chronic hepatitis, liver cirrhosis and diabetes mellitus, serum FT3 and FT4 levels were significantly lower than that in the controls. In thyroid diseases, serum FT3 levels varied parallel to other thyroid hormone levels. In primary hypothyroidism, however, serum FT3 levels were still lower than these in the controls after treatment with 1-thyroxine, whereas other thyroid hormone levels and TSH levels returned to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the accuracy of a quantitative kit radioimmunoassay for free thyroxine.

Experiments designed to determine the accuracy of the Corning Immophase Free T4 assay revealed that there was a marked perturbation of thyroxine binding to the serum proteins during the assay; binding of 125I-T4 to the immobilised T4 antibody in the absence of merthiolate increased considerably with buffer dilution of serum; and the free thyroxine concentration declined significantly during pregnancy. These changes in measured fT4 were not observed with an equilibrium dialysis-radioimmunoassay procedure. The assay was precise, easily performed, and as effective as the free thyroxine index (FTI) in diagnosing thyroid disease. We conclude that the assay does not provide an accurate quantitative estimation of serum fT4 concentration in samples with elevated TBG concentration and that the kinetic principles on which the assay is based are altered as serum binding-protein concentration is reduced (serum dilution). Both FTI and fT4 (Corning) data in pregnant patients should be interpreted with caution and with reference to clinical symptomatology and other thyroid function tests.

Serum free thyroxine concentrations in subjects with high circulating levels of thyroxine-binding globulin.

Serum free thyroxine (FT4) and thyroid hormone-binding protein concentrations were measured in pregnant women, stilboestrol-treated patients, and subjects with congenital thyroxine-binding-globulin (TBG) excess. In pregnant and stilboestrol-treated patients matched for TBG concentrations, serum FT4 concentrations measured by the Amerlex technique and by calculation, were reduced, as also was the total thyroxine (TT4)/TBG ratio. In congenital TBG excess Amerlex and calculated FT4 concentrations were normal whereas the TT4/TBG ratio was low. In contrast to the Amerlex method, FT4 concentrations by the Immophase procedure were normal in pregnant and stilboestrol-treated individuals and high in congenital TBG excess. We conclude that (i) reduced FT4 concentrations in pregnancy are related to an oestrogen effect rather than to some other pregnancy-associated factor, (ii) the TT4/TBG ratio gives a misleading indication of FT4 concentration in congenital TBG excess, and (iii) that when TBG concentrations are raised Immophase gives higher FT4 values than Amerlex or calculation when each is compared to FT4 values in their normal respective control group.

Serum free thyroxine concentrations in normal euthyroid subjects and ones with high serum thyroxine binding globulin concentration

Serum free thyroxine (fT4) was assayed by a commercial fT4 method in 30 normal euthyroid subjects, 19 pregnant females, 13 euthyroid subjects with high thyroxine binding globulin (TBG) and three with low or undetectable serum TBG concentration. In a number of these fT4 was also calculated on the basis of the application of the law of mass action to the binding situation. In states in which TBG was altered for congenital reasons both the experimentally determined and calculated fT4 were not significantly different from their respective means in the normal euthyroid population. Pregnant females had both lower experimental and theoretical free T4 concentrations. It is inferred from these data that TBG concentration per se is without effect on serum fT4 concentration.

Serum free thyroxine concentration and free thyroid hormone indices in normal pregnancy.

Serum free thyroxine (FT4) concentrations were shown to be significantly reduced at 36-38 weeks normal pregnancy, both as measured FT4 by the Amerlex method (P less than 0.001), and as calculated FT4 (P less than 0.001) using accepted molecular weight and affinity constant data for the binding proteins. Serum FT4 concentrations as determined by the Immophase method were normal at 36-38 weeks normal pregnancy. All methods gave normal serum FT4 concentrations in subjects taking the oral contraceptive pill. FT4I and FT3I, derived using the MAA T3 uptake-value, were higher than normal at 36-38 weeks pregnancy (P less than 0.001), whereas T4/TBG and T3/TBG were both reduced (P less than 0.001). The observation that serum FT4 concentrations may fall in late pregnancy, as demonstrated both by the Amerlex radioimmunoassay technique and by calculation, suggests that circulating FT4 may not be the sole determinant of thyroid status at this time. From a practical viewpoint, it is important to note that currently available direct and indirect methods of assessing serum FT4 concentrations produce different patterns of change in pregnancy.

Effect of carbamazepine, phenytoin and phenobarbitone on serum levels of thyroid hormones and thyrotropin in humans.

Patients on long-term treatment with either of the stereochemically related antiepileptic drugs phenytoin (DPH) or carbamazepine (CBZ) had similar changes in serum thyroid hormone concentrations. T4, FT4, FT4 index, T3, FT3, FT3 index and rT3 were reduced, whereas T3U and TSH were not significantly different from the reference group levels. Long-term phenobarbitone treatment had no convincing effect on the investigated parameters when used alone, but possibly potentiated the effect of CBZ. In patients starting on CBZ, T4 fell to a stable 70% of the basal level after 1--2 weeks. T3 decreased transitorily to 85% of the basal level. TSH showed a complementary but somewhat delayed transitory increase. T3U and TBG did not change significantly. The effect of CBZ and DPH can be explained by interference with thyroid hormone binding to TBG combined with enzyme-induced increased metabolic clearance rate of thyroid hormones without homeostatic maintenance of premedication levels of FT4 and FT3. We suggest that the regulated factor maintaining euthyroidism in these patients is the total quantity of thyroid hormones being degraded in the tissues per unit time. We conclude that serum concentrations of FT4 and FT3 do not reflect thyroid status adequately under all circumstances.

TOTAL AND FREE THYROXINE AND TRIIODOTHYRONINE IN NORMAL AND COMPLICATED PREGNANCY

Serum concentrations of total and free thyroxine (T4 and FT4) and total and free triiodothyronine (T3 and FT3) were measured in normal pregnant women, in patients with toxemia of pregnancy, and in patients with gestational trophoblastic disease (GTD). In normal pregnancy, FT4 and FT3 levels remained normal while T4 and T3 levels were elevated. In patients with pre-eclampsia, the mean serum T3 concentration was significantly lower than that of normal pregnancy and the serum FT3 concentrations in three out of nine patients were below the normal pregnancy range. The mean serum T4 and FT4 concentrations in patients with pre-eclampsia were, however, significantly higher than those in normal pregnant women. In patients with GTD without signs of hyperthyroidism, the mean serum total and free T4 concentrations were 43 and 92% higher than those in normal pregnancy (P less than 0.02), and many patients had levels above the range of values observed in normal pregnant women. The mean serum total and free T3 concentrations in GTD patients without signs of hyperthyroidism were not different from those of normal pregnancy (P less than 0.05). In the single GTD patient with hyperthyroid crisis, the s. erum FT4 concentration was within the range seen in GTD patients without signs of hyperthyroidism. Her serum FT3 concentration was, however, much higher than the ranges in normal pregnancy or in GTD patients without clinical hyperthyroidism. Higher than normal FT4 levels were found in patients with and without elevated hCG levels.

THYROID FUNCTION IN THE PRETERM FETUS

Measurements of serum total thyroxine (T4), free thyroxine (FT4), and/or immunoreactive thyrotropin (TSH) were conducted on 14 pairs of maternal and cord blood specimens obtained at the time of elective therapeutic abortion of 11- to 18-week pregnancies and on 21 paired maternal and fetal cord blood specimens collected at the time of spontaneous, premature delivery of 22- to 34-week pregnancies. T4 concentrations were elevated in all maternal samples to levels characteristic of pregnancy; mean values were similar at 11 to 18 and at 22 to 34 weeks and did not differ from the mean level reported previously at term. Mean maternal TSH concentrations also were similar at 11 to 18 weeks, 22 to 34 weeks, and at term. The mean FT4 concentration in maternal serum between 11 and 18 weeks was significantly higher than the level reported previously at term. Fetal serum T4 and FT4 concentrations were low between 11 and 18 weeks and increased progressively between 22 weeks and term. Fetal serum TSH concentrations were low between 11 and 18 weeks of pregnancy but seemed to increase abruptly between 18 and 22 weeks to levels characteristic of term infants. These data suggest that the maternal concentration of FT4 is higher early in pregnancy than at term, perhaps because of the higher blood levels of human chorionic thyrotropin in early pregnancy. They also indicate autonomous function of the fetal hypothalamic-pituitary control system as early as 12 weeks' gestation. The abrupt increase in fetal serum TSH between 18 and 22 weeks suggests rapid maturation of the fetal hypothalamic-pituitary unit during this period. The subsequent progressive increase in fetal FT4 concentration indicates an increasing thyroidal response to the TSH stimulus.