Fraction Of T4 Research Articles

The influence of free fatty acids on the free fraction of thyroid hormones in serum as estimated by ultrafiltration.

Thyroid hormones are displaced from their binding proteins in serum during nonthyroidal somatic illness, and FFA have been claimed to contribute. It seems mandatory to evaluate this effect using techniques for the measurements of serum free thyroid hormones in which serum remains undiluted. We measured the effect of 7 common human FFA on the free fraction of T4, T3 and rT3 in serum from healthy subjects using an ultrafiltration technique by which serum is diluted only minimally. In addition we measured the effect of oleic acid on the free fractions of the iodothyronines in pooled serum from healthy subjects and in pooled serum from patients with nonthyroidal illness. All FFA tested were able to displace both T4, T3 and rT3, but to a varying degree, arachidonic and linoleic acid being the most potent ones. A 20% increase in the free fractions of T4, T3 and rT3, respectively, was obtained by adding between 1.7-3.3 mmol/l, 1.3-4.6 mmol/l and 1.0-2.4 mmol/l of the different FFA. A serum pool obtained from patients with nonthyroidal somatic illness was more sensitive to oleic acid than a serum pool obtained from healthy subjects, since 2-3 times less oleic acid was necessary to induce a 20% increase in the free fractions of thyroid hormones. It is concluded that FFA are able to displace both T4, T3 and rT3 from their serum binding proteins in healthy subjects as well as in patients with nonthyroidal illness. However, serum from patients with nonthyroidal illness was more sensitive to the displacing activity of oleic acid than serum from healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of thymosin on the formation of the functional activity of the adrenals in mice.

1. The administration of mice, thymectomized at the third day of age, of T3 fraction 5 in the first month of life, leads to the formation of reduced function of the adrenals in male and female adult animals. 2. The administration of T3 in vitro suppresses the hormonal function of the adrenal cortex in male and female mice. 3. The administration of T3 to adult male mice in vivo reduces the production of adrenal cortical glucocorticoids. 4. The significant activity which T3 manifests in relation to the adrenals, makes it possible to assume that the diverse influence of the thymus on the endocrine system may be mediated by this preparation.

ANOMALOUS BINDING CHARACTERISTICS OF HUMAN THYROXINE BINDING GLOBULIN DUE TO A DILUTION‐DEPENDENT SEPARATION ARTEFACT

Contrary to the accepted view, a recent study using Sephadex column separation suggested that thyroxine binding globulin (TBG) binds T4 and T3 with similar affinity, but with a much larger capacity for T4 than T3. We have evaluated this finding by comparing this separation method with equilibrium dialysis, taking account of the effect of serum dilution with each method. Estimates of free T4 fraction by equilibrium dialysis (with magnesium chloride precipitation) were valid over a wide range of serum dilutions. In contrast, Sephadex column separation gave a major overestimate of free hormone (underestimate of binding) in less diluted serum, indicating that this method cannot be used to establish a value for T4 affinity independent of serum dilution. Such a systematic error will result in a greater underestimate of affinity for the ligand with higher affinity when two ligands are compared at a single serum dilution. By equilibrium dialysis at 37 degrees C, the affinity of T4 for TBG was approximately 13-fold higher than that of T3, while the capacity of TBG for both T4 and T3 was close to the concentration of immunoreactive TBG. The previous report of similar T4 and T3 affinities appears to be due to a dilution-dependent underestimate of T4 affinity inherent in Sephadex column separation. Direct comparison of binding kinetics of various ligands requires a separation method that is valid over a wide range of binding protein concentrations.

The effect of serum free fatty acid on serum free thyroid hormone fractions in low T3 syndrome

We studied the role of serum free fatty acid (FFA) in the elevation of serum dializable fraction of T4 (DFT4) and evaluated the serum free T4 (FT4) level in low T3 syndrome. Serum DFT4 and DFT3 were measured by equilibrium dialysis method with phosphate buffer, and serum FFA concentration was obtained by gas chromatography. In patients with nonthyroidal systemic illnesses who showed reduced serum total T3 (TT3) and normal total T4 (TT4) (low T3 group, TT3 48 +/- 14 ng/dl, n = 10), mean (+/- SD) DFT4 value (0.032 +/- 0.05%) was significantly higher than that of the group of systemic illnesses with normal TT3 and TT4 (normal T3 group, TT3 79 +/- 7 ng/dl, n = 10). Mean TT4 value of low T3 group (6.5 +/- 1.0 micrograms/dl) was lower than that of normal T3 group (8.6 +/- 2.4 microgram/dl, p less than 0.02). There was no difference in mean absolute FT4 (AFT4) value between the two groups (2.07 +/- 0.46 vs 2.19 +/- 0.53 ng/dl). On the other hand, there was no significant difference in DFT3 value between the groups (0.274 +/- 0.043 vs 0.247 +/- 0.035%), and mean AFT3 of low T3 group (1.29 +/- 0.39 pg/ml) was low than that of normal T3 group (1.92 +/- 0.26 pg/ml, p less than 0.01). In cases of low and normal T3 groups (n = 20), serum thyroxine binding globulin (TBG) concentration had a negative correlation with DFT3 (r = -0.707, p less than 0.001), but not with DFT4. Although there were no significant differences in serum albumin and TBG concentrations between the two groups, the mean serum total FFA concentration and molar ratio of FFA to albumin in low T3 group (579 +/- 249 microM and 1.31 +/- 0.61) were significantly higher than those in normal T3 group (345 +/- 170 microM and 0.75 +/- 0.32, p less than 0.05 and less than 0.025, respectively). All of FFA concentrations in low T3 group, especially oleate, were higher than those in normal T3 group. Moreover, the higher the total FFA concentration was, the greater was the percent fraction of oleate. DFT4 values were significantly increased by the addition of 1 mM oleate to the sera of low T3 group, and this effect was more marked in the sera of the patients with lower albumin concentration.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of thyroxine (T4)-binding serum proteins in oleic acid-induced increase in free T4 in nonthyroidal illnesses.

We studied the effects of various concentrations of oleic acid (0.1-3.3 mM), such as are often found in the serum of patients with nonthyroidal illness, on the dialyzable (free) fraction of T4 (DFT4) in three types of serum samples: pooled normal serum (PNS), pooled pregnancy serum (PPS), and pooled serum of hospitalized patients (PSHP). The samples were extracted with diethyl ether to remove endogenous fatty acids before being tested in the DFT4 assay. Oleic acid caused only a moderate increase in DFT4 in PNS; a significant (greater than 2 SD above control) increase (15%) was found with 2.0 mM oleic acid, and the maximal dose of oleic acid (3.3 mM) caused a 33% increase in DFT4. However, the DFT4-increasing effect of oleic acid was enhanced (increase in DFT4 of 33% caused by 0.9-1.2 mM oleic acid) when the serum tested had low (0.5 times normal) albumin and prealbumin concentrations with either normal (50% PPS) or half-normal TBG (50% PNS). The effect of oleic acid in 100% PSHP was significantly (P less than 0.005) greater than that in 100% PNS, and it was close to that in 50% PNS (increase in DFT4 with 3.3 mM oleic acid, 118% in PSHP vs. 98% in 50% PNS). Normalization of serum albumin in PSHP by adding exogenous albumin markedly reduced the DFT4-increasing effect of oleic acid; the maximal increase in DFT4 of 64% with 3.3 mM oleic acid in albumin-normalized PSHP was equalled with 1.3 mM oleic acid in unmodified PSHP. The data suggest that the serum concentrations of albumin and other T4-binding proteins are important in modulating the DFT4-increasing effect of oleic acid and that oleic acid may contribute to the reduced serum binding of T4 in nonthyroidal illness.

Abnormal thyroid hormone binding to serum proteins in ob/ob and db/db genetically obese mice.

Sera from ob/ob and db/db genetically obese mice exhibited abnormal nonspecific (no antibody present) binding measurements in T4 and T3 RIAs employing dextran-charcoal separations. They also showed decreased charcoal uptake compared to sera of lean controls in a conventional charcoal T4 uptake binding test. After correction for the abnormal nonspecific binding and after extraction of serum, mean serum T4 concentrations were similar in control and ob/ob mice. Mean serum T3 concentrations differed significantly (85 ng/dl in controls and 178 ng/dl in ob/ob) when a correction for altered binding in the T3 assay was made, but not when extracted serum was assayed (109 ng/dl in lean and 124 ng/dl in ob/ob). Dialyzable fractions of T4 and T3 were significantly reduced in both ob/ob and db/db mice. Free T4 concentrations were 0.82 +/- 0.05 (+/- SE) ng/dl in control and 0.61 +/- 0.05 ng/dl in ob/ob sera (P less than 0.01). Polyacrylamide gel electrophoresis showed increased binding of tracer T4 and T3 in ob/ob and db/db sera to a postalbumin with mobility similar to that of human T4-binding globulin. In ob/ob sera, this appeared to result from an increased binding capacity of the postalbumin. After in vivo iv injection of tracer T4 and T3 to ob/ob and lean control mice, analysis of tissue and plasma radioactivity showed that, except for T4 in cerebral cortex, tissue to plasma T4 and T3 ratios were lower in cerebral cortex, cerebellum, and liver of ob/ob mice. In summary, these data show increased binding of T4 and T3 to a postalbumin in two strains of genetically obese mice and, in the ob/ob strain, complex relationships between tissue and serum concentrations of thyroid hormones.

Improved ultrafiltration method for simultaneous measurement of free thyroxin and free triiodothyronine in serum.

We describe a new ultrafiltration method for measuring concentrations of free thyroxin (FT4) and free triiodothyronine (FT3). Serum containing [131I]T4 and [125I]T3 is diluted 10-fold in phosphate buffer (500 mmol/L, pH 7.4 at 37 degrees C), then passed through a YMT membrane in an Amicon MPS-1 centrifugal ultrafiltration device. Radioactive iodide and protein-bound thyronines are separated from FT4 and FT3 in the ultrafiltrate by use of a Sephadex G-25 microcolumn. In normal controls, the fraction of T4 that passes into the ultrafiltrate is 0.021 +/- 0.006% (mean +/- SD), FT4 is 19.6 +/- 6.5 ng/L, the fraction of T3 that passes into the ultrafiltrate is 0.18 +/- 0.5%, and the FT3 is 2.03 +/- 0.50 ng/L. Intra-assay precision (CV) is 5.4% for FT4 and 4.2% for FT3; the respective interassay CVs are 10.1% and 8.0%. In various groups of patients with thyroid disease and other conditions that influence serum T4 and T3 concentrations, FT4 by ultrafiltration correlated with FT4 measured by equilibrium dialysis (r = 0.84, p less than 0.001) and FT3 by ultrafiltration correlated with FT3 measured by the Diagnostic Products RIA kit (r = 0.87, p less than 0.001). The accuracy, reproducibility, speed, and simplicity of the ultrafiltration method compared favorably with the more cumbersome method of equilibrium dialysis.

Functional characterization of human thymocytes: a limiting dilution analysis of precursors with proliferative and cytolytic activities.

In this report we have analyzed the pool size of human thymocytes capable of proliferating or mediating cytolytic activity. Furthermore, the relationship between these functional capabilities and cell surface antigen expression was studied. Graded numbers of human thymocytes were plated under limiting dilution conditions with irradiated human spleen cells (as a source of feeder cells) and phytohemagglutinin (PHA) in the presence of a saturating concentration of interleukin 2. Cell proliferation, which was evaluated after 20 days of culture, was usually compared with the proliferation of peripheral blood T cell populations cultured under identical conditions. Although essentially all peripheral blood T cells were clonogenic, only 3 to 8% of thymocytes proliferated. Of proliferating microcultures, 48 to 86% showed cytolytic activity in a PHA-dependent assay, whereas 26 to 83% killed the NK-sensitive target cell K-562 in the absence of added lectin. Similar frequency analysis of functional precursors was performed on thymocyte subsets selected according to their expression of T3, T6, T4, and T8 antigens. All precursors of proliferating cells (PTL-P) were found in the T3+ subset. From the comparison of the percentages of total thymocytes capable of proliferation and the proportion of cells brightly stained with anti-T3 antibody, it was evident that only a fraction of T3+ cells was clonogenic. Although the large majority of PTL-P was found in the T6- subpopulation, a small fraction of functional precursors was detected in the T6+ subset. When thymocytes were fractionated according to T4 or T8 antigen expression, it was found that 80 to 90% of the recovered PTL-P were confined to the T4+ fraction, whereas only 20 to 28% of the recovered PTL-P were present in the T8+ subset. Analysis of the precursors of cytolytic T lymphocytes (CTL-P) in thymocyte populations fractionated according to T4 or T8 antigen expression showed that 70 to 90% of the recovered CTL-P were found in the T4+ fraction and 17 to 30% were in the T8+ subset. Because approximately 80% of proliferating T4+ thymocytes had CTL activity (as compared with less than 5% in peripheral blood T4+ lymphocytes), it appears that the subset distribution of thymic CTL-P differs from that of peripheral blood T cells.

Serum free T4, T3, rT3, 3,3'-diiodothyronine and 3',5'-diiodothyronine measured by ultrafiltration.

A simple and accurate method for estimation of the free fractions (FFT) of T4, T3, rT3, 3,3'-diiodothyronine (3,3'-T2) and 3',5'-diiodothyronine (3',5'-T2) in serum is presented. The method is based on ultrafiltration of serum pre-incubated with tracers of high specific activity, followed by purification of the ultrafiltrate on small Sephadex columns. The addition of tracer only dilutes serum negligible (about 5%) and the ultrafiltration procedure only removes about 7% of the volume of serum, thus probably not disturbing the equilibrium between the free and protein bound fraction of iodothyronine. Progressive reduction of tracer to less than 10% of the amount usually used did not reduce the FFT of any of the iodothyronines. In contrast, addition of T4 to serum led to an increase of all FFTs except that of 3',5'-T2. These data suggest that FFT of T4, T3, rT3 and 3,3'-T2 primarily is determined by the amount of T4 present in serum and that significant amounts of these iodothyronines are bound to TBG, whereas 3',5'-T2 possibly primarily is bound to albumin. The median FFT of T4, T3, rT3, 3,3'-T2 and 3',5'-T2 in serum from euthyroid subjects (n = 38) was: 0.030, 0.29, 0.14, 1.10 and 1.07%, respectively. The corresponding median free concentrations in pmol/l were: 30, 4.79, 0.59, 0.44 and 0.77, respectively. Pregnant women in 3rd trimester had normal levels of free T4, free T3 and free rT3, whereas the median free 3,3'-T2 was reduced in contrast to elevated median free 3',5'-T2.(ABSTRACT TRUNCATED AT 250 WORDS)

The behavior of the triiodothyronine/thyroxine (T3/T4) ratio in normal individuals, and its implications for the regulation of euthyroidism.

In order to examine the significance of differences in the triiodothyronine/thyroxine (T3/T4) ratio in the control of euthyroidism in a normal population, we measured the serum T3, T4 and FT4 index (FT4I) in 121 healthy men and 68 women. The correlation between T3 and T4 was poor (r = 0.24), suggesting that most of the natural variation in T3 among normal individuals occurs independently of the T4 level. There was, however, a strong inverse correlation (r = 0.59, p less than 0.001) between T3/T4 ratio and FT4I. This correlation reflected a constancy in mean T3 at different levels of T4 such that the T3 changed by only 0.35 nmol/l (22%) throughout the range of normal T4. Furthermore, the T3/T4 ratios of 48 hypothyroid individuals with subnormal T4 represented a simple extension of the relationship found in the healthy individuals, indicating that the rise in T3/T4 classically associated with falling T4 in primary hypothyroidism is merely part of a continuous process of change which begins in euthyroidism. It is proposed that the relationship between T3 and T4 is finely controlled in healthy individuals in such a way that differences in hormone activity due to the wide range of serum T4 among normals may be buffered by systematic adjustment of the T3/T4 ratio. Those with the highest T4 appear to maintain euthyroidism with a minimal T3/T4 ratio. The remainder, with T4 levels towards the lower limit of normal, are subject to a progressive increase in the T3 fraction and may depend on it to remain euthyroid.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of mefenamic acid on plasma protein-thyroid hormone interaction, monodeiodination of thyroxine, urinary excretion of tri-iodothyronine and thyrotropin regulation.

A single oral dose of mefenamic acid significantly depressed plasma thyroxine (T4) within 3 h in man. Similarly, mefenamic acid depressed plasma T4 within 3 h in thyroidectomized, T4-maintained rats. Plasma free fractions of T4 and tri-iodothyronine (T3) increased significantly after a single oral administration of mefenamic acid in man. In vitro addition of mefenamic acid to plasma also increased the plasma free fraction of T4. Three times more T3 was excreted into urine after an acute administration of mefenamic acid. In vitro conversion of T4 to T3 by liver homogenate was stimulated when T4 was displaced from plasma binding protein by mefenamic acid. Pituitary content of T3 increased when mefenamic acid displaced T4 and T3 from the binding protein. Simultaneously, thyrotropin (TSH) secretion in response to thyrotropin releasing hormone (TRH) was completely blocked by mefenamic acid. Prolactin release in response to TRH and luteinizing hormone (LH) and follicle stimulating hormone (FSH) release in response to luteinizing hormone releasing hormone (LH-RH) were not affected by mefenamic acid. It is concluded that mefenamic acid displaces T3 and T4 from their plasma binding protein and more T4 and T3 are available to peripheral tissues for excretion, degradation and TSH regulation.

Thyroid hormone metabolism and the source of plasma triiodothyronine in 2-week-old rats: effects of thyroid status.

Earlier studies have shown larger increments in serum T3 in 2-week-old congenitally hypothyroid rats than in euthyroid controls after injections of small doses of T4. Since hepatic and renal 5'-deiodination of T4 to T3 in vitro (5' D-I) is reduced during the neonatal period and in hypothyroidism, those results suggest that there may be major changes in the distribution and metabolism of T3 or that an alternative enzymatic pathway is the predominant source of extrathyroidally produced T3 in these rats. The alternative pathway, 5' D-II, is a relatively minor source of serum T3 in adult euthyroid rats, but the contribution of this pathway to the extrathyroid T3 pool during the neonatal period and in hypothyroxinemia is not known. Consequently, we studied [125I]T4 and [131I]T3 kinetics and fractional T4 to T3 conversion in 2-week-old euthyroid and hypothyroid rats and then explored the source of circulating T3 by manipulating 5' D-I activity with propylthiouracil and that of 5' D-II with thyroid hormone. The plasma clearance rate of T4 was increased in hypothyroid rats, a difference entirely accounted for by the faster fractional rate of irreversible removal in the hypothyroid pups. Plasma clearance rate of T3 was reduced in hypothyroid rats owing to the reduced volume of distribution of T3. Fractional T4 to T3 conversion was 2- to 3-fold higher in euthyroid or hypothyroid neonates than in adult rats. In euthyroid rats the serum concentration of T4 was 36 +/- 1 (SEM) ng/ml and that of T3 0.61 +/- 0.03 ng/ml, and the production rates were 432 and 159 ng day-1 30 g-1 BW for T4 and T3, respectively. About 80% of the T3 in euthyroid neonates was produced extrathyroidally . These findings are inconsistent with hepatic and renal 5' D-I being the main source of serum T3 in 2-week-old rats. In fact, liver and kidney 5' D-I activities were 40% and 65% of the corresponding adult values in euthyroid neonates, and in hypothyroid pups were further reduced to 15% and 17%. In contrast, 5' D-II, previously reported to be high in central nervous tissue and pituitary, was 7-10-fold higher in brown adipose tissue (BAT) of hypothyroid pups than in that of euthyroid ones.(ABSTRACT TRUNCATED AT 400 WORDS)

Acquisition of specific cytotoxic activity by human T4+ T lymphocytes in culture.

Mature human T lymphocytes can be separated by monoclonal antibodies OKT4 and OKT8 according to their surface phenotypes into T4+T8- and T4-T8+ subsets. From short-term experiments using bulk cultures, the helper/inducer function has been assigned to the T4+T8- subset and the cytotoxic/suppressor function to the T4-T8+ subset. Thus if T lymphocytes are separated after stimulation in a mixed lymphocyte reaction (MLR), the entire cytotoxic activity is found in the T4-T8+ fraction whereas the T4+T8- fraction shows no detectable cytotoxicity. If, however, T lymphocytes are cloned after MLR and grown in long-term culture, a surprisingly large fraction of T4+ T lymphocyte clones (TLC) shows cytotoxic activity. Here we report that T4+ TLC can acquire specific cytotoxicity during in vitro cultivation.

Effect of danazol on thyroid function in postmenopausal women.

During treatment with danazol the serum concentration of thyroxin-binding globulin (TBG) decreases. This effect is probably a direct effect on TBG production at the cellular level. In order to exclude an indirect effect on TBG production via the well known suppressing effect of danazol on serum estrogen concentrations, the following study was performed. Twelve healthy female volunteers, who were at least 3 years past the menopause and with serum-estradiol levels below 100 pmol/l, were treated with danazol in dosages of 400, 600 or 800 mg daily. The concentrations of TBG, TSH, total thyroxin (T4), total triiodothyronine (T3) and free dialysable fractions of T4 and T3 were determined, before, and after 2 and 4 weeks of medications. The serum concentrations of TBG, total T4 and T3 decreased. The TSH concentration and the free dialysable fraction of T4 were essentially unaltered after 2 weeks but the TSH had decreased slightly and free T4 increased slightly after 4 weeks. The free dialysable fraction of T3 decreased transiently at 2 weeks. All the observations proved to be independent of the three dosages of danazol applied in this study. In conclusion, danazol treatment influences available tests of thyroid function by reducing the concentration of TBG. This is most probably a direct effect of the drug, and it is clearly independent of the effect on estrogen production. Clinically there is no evidence of a decreased effect of thyroid hormones on the target organs.

Effects of a large dose of retinol or retinoic acid on the thyroid hormones in the rat.

The daily food intake of a large dose of retinol (as palmitate) or retinoic acid (as all-trans retinoic acid) modifies numerous parameters of the thyroidal status in the rat. There were decreases of the serum total thyroxine (TT4) and triiodothyronine (TT3), and of the biological half-life of T4, while there were increases of the dialyzable fractions of T4 and T3 and of the apparent distribution space of T3. The possible causes of these changes are discussed.

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.

Thyroid function in Gunn rats with genetically altered thyroid hormone catabolism.

Abstract. Due to a congenital deficiency in uridine diphosphate glucuronosyl transferase (UDP-GTase), Gunn rats display an impaired biliary elimination of both bilirubin and thyroid hormones, resulting in hyperbilirubinaemia and hyperthyroxinaemia. They also present a pigmented thyroid gland. In order to assess the effect of the hyperthyroxinaemia on the regulation of the thyroid function, the [125I]thyroid uptake and distribution into soluble proteins, the [127I]thyroid soluble content, the levels of circulating T4, total and free, T3, reverse T3 (rT3) and TSH as well as the TSH response to TRH have been determined in Gunn (G) and Wistar (W) rats aged 3 to 56 weeks. Gunn rats possess a goitre with increased soluble [127I]-iodine content. The [125I]thyroid uptake and incorporation into soluble proteins were similar in both strains, but the DIT fraction was higher, whereas the MIT, T4 and T3 fractions were lower compared to control rats. Total thyroxinaemia was greatly increased in Gunn rats as expected (G:5.1–9.1 vs W:3.1–4.6 μg/dl) whereasfree thyroxinaemia was increased only by 25–50%. The differences in total-T4 and bilirubin serum levels between Gunn and Wistar rats 6 to 56 weeks old were found to be in direct correlation. In addition, Gunn rats presented normal serum T3 levels, but increased rT3 (G: 0.10–0.45 vs W:<0.03–0.27 ng/ml) and TSH (G:0.33–0.75 vs W:0.11–0.43 ng/ml) serum levels. The TSH response to TRH was however normal, but the return to basal values was delayed in comparison to Wistar rats. Evolution of thyroid parameters with age was similar in both strains, i.e. opposite variations in T3 and rT3 serum values during the post-natal period and decreasing serum T4 concentrations, pituitary TSH content and TSH response to TRH during the adult life. In conclusion, the association of hyperthyroxinaemia with decreased T3/rT3 serum ratio suggests that Gunn rats may have, in addition to the impaired biliary excretion of iodothyronines, a modified T4 deiodination pattern with probably increased rT3 formation. A diminished T4 availability and/or a decreased T4 to T3 conversion in the thyrotrophe cell might explain the normal TSH response to TRH. These data reflect a partial peripheral resistance to the hyperthyroxinaemia, which may represent an adaptation mechanism.

Serum free thyroxine and triiodothyronine concentrations in subacute thyroiditis.

Serum absolute free T4 (AFT4) and T3 (AFT3) concentrations were studied in 10 patients with subacute thyroiditis whose total serum T4 levels were elevated, and values were compared with those obtained in 10 patients with untreated Graves' disease, whose total serum T4 concentrations were elevated to the same level as in the former group. The mean (+/- SD) basal metabolic rate in patients with subacute thyroiditis was 16 +/- 14.8%, significantly (P less than 0.001) lower than that in patients with Graves' disease (48.7 +/- 15.7%). Serum T4-binding globulin concentrations measured by RIA were normal and did not differ from those in Graves' disease patients. The percentage of free T4 and AFT4 were both elevated in subacute thyroiditis to a degree comparable to that seen in Graves' disease. The serum total T3, serum free T3 fraction and AFT3 were also elevated, but both total T3 and AFT3 were significantly (P less than 0.05 and P less than 0.05, respectively) lower than in Graves' disease patients. Therefore, the ratios of T3 to T4 and AFT3 to AFT4 were significantly (P less than 0.01 and P less than 0.01, respectively) lower than in Graves' disease patients. These results indicate that the significantly lower basal metabolic rate and milder manifestations of thyrotoxic symptoms in subacute thyroiditis than in Graves' disease might be explained by the low ratios of T3 to T4 and AFT3 to AFT4 as well as the short duration of chemical hyperthyroidism.

Relationship of altered thyroid hormone indices to survival in nonthyroidal illnesses.

SUMMARYAlthough alterations of serum thyroid hormone indices are frequent in nonthyroidal illnesses, their relationship to survival is poorly defined. Consequently, the prevalence and prognostic relevance of alterations in thyroidal indices were evaluated prospectively in 195 patients requiring intensive medical therapy and in 75 critically ill patients with serum total T4 (TT4) levels below 3 μg/dl. In the 195 patients, serum total T3 (TT3) and TT4 levels were reduced in 69% and 43% respectively. Decreased TT4 levels had the highest correlation with mortality (P < 0·001) and correctly predicted outcome in 70% of patients. Other thyroidal indices, which were significantly different between survivors and nonsurvivors, correlated with TT4 and did not contribute independently to prediction accuracy when assessed by discriminant function analysis.In seventy‐five patients with TT4 levels below 3 μg/dl, the nadir TT4 level appeared a median of 9 days (range 1–28) after hospital admission. The nonsurvivors lived a median of 6 days (range 0–42) and the survivors were discharged a median of 20 days (range 4–55) after the TT4 nadir. Only an increased free fraction of T4 (FFT4) was found to correlate significantly with mortality and contribute to prediction accuracy.An inhibition of serum T4 binding to carrier proteins could account for both the decreased serum TT4 and the increased FFT4 values. Serum TT4 and/or FFT4 levels may be useful in assessing the severity and predicting the clinical outcome of acute critical nonthyroidal illnesses.

Low protein-high carbohydrate diet induces alterations in the serum thyronine-binding proteins in the rat.

The serum T3 concentration was increased in 8-week-old lean Zucker rats fed a low protein-high carbohydrate diet for 2 weeks. This increase was secondary to the generation of a binding protein migrating in the postalbumin zone in polyacrylamide gel electrophoresis employing 125I-labeled T3 and is termed rat thyronine-binding globulin. The presence of this T3-binding protein in serum resulted in a marked decrease in the percent free T3 assessed by equilibrium dialysis and a normal free T3 concentration. An increase in the binding of T4 in the postalbumin zone was also observed, but no changes in the dialyzable fraction of T4 or the total and free T4 concentrations occurred. In contrast to these findings in lean Zucker rats fed the low protein-high carbohydrate diet, no change in the pattern of 125I-labeled T3 and T4 binding, the dialyzable fraction of T3 or T4, or total and free T3 or T4 concentrations were observed in the obese Zucker rats fed this diet. The present findings suggest that diet-induced alterations in thyroid hormone-binding proteins must be considered in the interpretation of data which involve alterations in total thyroid hormone concentrations in serum and their role in affecting tissue metabolism.