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PubMed1973

Effects of replacement doses of sodium L-thyroxine on the peripheral metabolism of thyroxine and triiodothyronine in man.

Studies of the effect of L-thyroxine administration (0.3 mg daily for 7-9 wk) on the peripheral metabolism of (131)I-labeled triiodothyronine (T(3)) and (125)I-labeled thyroxine (T(4)) and on the concentration and binding of T(4) and T(3) in serum were carried out in 11 euthyroid female subjects. Administration of L-thyroxine led to consistent increases in serum T(3) concentration (137 vs. 197 ng/100 ml), T(3) distribution space (39.3 vs. 51.7 liters), T(3) clearance rate (22.9 vs. 30.6 liters/day) and absolute T(3) disposal rate (30 vs. 58 mug/day), but no change in apparent fractional turnover rate (60.3 vs. 60.6%/day). The proportion and absolute concentration of free T(3) also increased during L-thyroxine administration. Increases in serum total T(4) concentration (7.3 vs. 12.8 mug/100 ml) and in both the proportion and absolute concentration of free thyroxine also occurred. In five of the subjects, the kinetics of peripheral T(4) turnover were simultaneously determined and a consistent increase in fractional turnover rate (9.7 vs. 14.2%/day), clearance rate (0.84 vs. 1.37 liters/day), and absolute disposal rate (64.2 vs. 185.0 mug/day) occurred during L-thyroxine administration. Despite these increases in the serum concentration and daily disposal rate of both T(4) and T(3), the patients were not clinically thyrotoxic. However, basal metabolic rate (BMR) values were marginally elevated and, as in frank thyrotoxicosis, T(4)-binding capacities of thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA) reduced, suggesting that subclinical thyrotoxicosis was present. Thus, the often recommended replacement dose of 0.3 mg L-thyroxine daily may be greater than that required to achieve the euthyroid state. The studies have also provided additional evidence of the peripheral conversion of T(4) to T(3) in man and have permitted the calculation that approximately one-third of exogenously administered T(4) underwent deiodination to form T(3). To the extent that a similar fractional conversion occurs in the normal state, it can be calculated that a major fraction of the T(3) in serum derives from the peripheral deiodination of T(4) and that only a lesser fraction derives from direct secretion by the thyroid gland.

Adult↗
PubMed2005

Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone.

BACKGROUND: Substituting part of the dose of l-thyroxine with small but supraphysiologic doses of liothyronine in hypothyroid patients has yielded conflicting results. OBJECTIVE: To evaluate combinations of L-thyroxine plus liothyronine in hypothyroid patients that match the proportions present in normal secretions of the human thyroid gland. DESIGN: Randomized, double-blind, crossover trial. SETTING: Academic research hospital. PARTICIPANTS: 28 women with overt primary hypothyroidism. INTERVENTION: Crossover trial comparing treatment with l-thyroxine, 100 microg/d (standard treatment), versus treatment with L-thyroxine, 75 microg/d, plus liothyronine, 5 microg/d (combination treatment), for 8-week periods. All patients also received L-thyroxine, 87.5 microg/d, plus liothyronine, 7.5 microg/d (add-on combination treatment), for a final 8-week add-on period. MEASUREMENTS: Primary outcomes included serum thyroid hormone levels, results of quality-of-life and psychometric tests, and patients' preference. Multiple biological thyroid hormone end points were studied as secondary outcomes. RESULTS: Compared with standard treatment, combination treatment led to lower free thyroxine levels (decrease, 3.9 pmol/L [95% CI, 2.5 to 5.3 pmol/L]), slightly higher serum levels of thyroid-stimulating hormone (increase, 0.62 mU/L [CI, 0.01 to 1.23 mU/L]), and unchanged free triiodothyronine levels. No improvement was observed in the other primary and secondary end points after combination treatment, with the exception of the Digit Span Test, in which the mean backward score and the mean total score increased slightly (0.6 digit [CI, 0.1 to 1.0 digit] and 0.8 digit [CI, 0.2 to 1.4 digits], respectively). The add-on combination treatment resulted in overreplacement. Levels of thyroid-stimulating hormone decreased by 0.85 mU/L (CI, 0.27 to 1.43 mU/L) and serum free triiodothyronine levels increased by 0.8 pmol/L (CI, 0.1 to 1.5 pmol/L) compared with standard treatment; 10 patients had levels of thyroid-stimulating hormone that were below the normal range. Twelve patients preferred combination treatment, 6 patients preferred the add-on combination treatment, 2 patients preferred standard treatment, and 6 patients had no preference (P = 0.015). LIMITATIONS: Treatment with L-thyroxine, 87.5 microg/d, plus liothyronine, 7.5 microg/d, was an add-on regimen and was not randomized. CONCLUSIONS: Physiologic combinations of L-thyroxine plus liothyronine do not offer any objective advantage over l-thyroxine alone, yet patients prefer combination treatment.

Adolescent↗
PubMed1982

Thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) measurement, compared with the conventional T3 uptake in the diagnosis of thyroid disease.

An electroimmunoassay for the determination of thyroxine binding prealbumin is described. The diagnostic efficiency of the assay when used in conjunction with the serum thyroxine as a thyroxine: thyroxine binding prealbumin ratio, is compared with the conventional free thyroxine index and the more recently developed thyroxine: thyroxine binding globulin ratio. The population studied included euthyroid, hypothyroid and hyperthyroid patients and also those who were either pregnant or receiving oral contraceptive therapy. Despite recent evidence establishing the theoretical/practical advantages of using a direct measurement for thyroid binding proteins rather than an indirect method (tri-iodothyronine uptake), results obtained from this study suggest that, for the majority of patients requiring biochemical assessment, the free thyroxine index is still the superior discriminator of thyroid abnormality.

Female↗
PubMed1989

Evidence for a slow tissue adaptation to circulating thyroxine in patients with chronic L-thyroxine treatment.

We measured serum procollagen-III-peptide in 67 women with long-term L-thyroxine treatment and compared the results with age-matched controls. The strong correlation between serum free thyroxine and procollagen-III-peptide concentrations previously found after 6 months of L-thyroxine treatment was not found after long-term treatment. There were slightly higher procollagen-III-peptide concentration values in those chronically treated patients who had high free thyroxine levels but this increase was less marked than in patients previously studied after short-term treatment. An increase in procollagen-III-peptide concentration reflects an increased biosynthesis of collagen III, which is present in connective tissues throughout the body, and our findings may be explained by slow tissue adaptation to increased levels of thyroxine. We conclude that the increased thyroxine levels found in L-thyroxine-treated patients are of less clinical importance than thought previously. We also conclude that peripheral markers of thyroid hormone peripheral effects such as procollagen-III-peptide may be of less use than thought previously due to this slow tissue adaptation to changes in thyroxine concentration.

Adaptation, Physiological↗
PubMed1984

Relevance of increased serum thyroxine concentrations associated with normal serum triiodothyronine values in hypothyroid patients receiving thyroxine: a case for "tissue thyrotoxicosis".

Fifteen patients receiving standard thyroxine replacement therapy (100-200 micrograms daily) for primary hypothyroidism and who had persistently raised free thyroxine concentrations in their serum were investigated to see whether the dose being given was too high. In addition to the usual thyroid hormone assays systolic time intervals (which indicate left ventricular contractility) were calculated as accurate reflectors of tissue thyroid activity. All patients showed the expected increased free and total thyroxine concentrations; but mean total and free concentrations of triiodothyronine were normal, while reverse triiodothyronine values were raised. Mean systolic time intervals were significantly reduced as compared with normal and fell within the thyrotoxic range. Seven patients subsequently had their doses of thyroxine reduced by 50 micrograms daily and were reinvestigated one month later. All showed significant falls in circulating thyroxine and triiodothyronine concentrations and an increase in mean systolic time intervals to the normal range. In patients receiving thyroxine replacement therapy for primary hypothyroidism a raised serum thyroxine concentration may indicate tissue thyrotoxicosis and should prompt a reduction of the thyroxine dose.

Adult↗
PubMed2003

Pretreatment with thyroxine (10-(8) parts by weight) enhances a 'curative' effect of homeopathically prepared thyroxine (10-(13)) on lowland frogs.

We studied the influence of a moderate homeopathically prepared thyroxine dilution (final concentration in the basin water 10-(13) parts by weight) on the metamorphosis of lowland Rana temporaria which had been hyperstimulated with thyroxine. Two groups of animals were pretreated by immersing them in a molecular thyroxine dilution (10-(8) parts by weight). This pretreatment speeds up development, as is well known. In accordance with the homeopathic/isopathic idea of detoxication or cure, the same hormone was then diluted and agitated in successive steps for further treatment. This homeopathically prepared dilution was administered at 24-hour intervals to one of the groups. An analogously prepared blank solution was used for the control group. Our hypothesis, which was derived from earlier studies, was that animals treated with the test solution would metamorphose more slowly than the control animals, i.e. that the homeopathically prepared thyroxine would have a 'curative' effect. In this new series of experiments this hypothesis was examined by 3 independent researchers. In the experiments carried out by 2 of the 3 researchers the number of animals that reached the four-legged stage at defined points in time was smaller in the group treated with homeopathically prepared thyroxine. In the third laboratory no difference was found between the groups. However, the overall inhibiting effect was statistically significant and more pronounced than in earlier, less promising studies and in parallel experiments in which nonprestimulated animals had been used. Other studies carried out by the 3 researchers involved animals from highland biotopes, where the natural environment probably induces a greater sensitivity towards thyroxine or higher thyroxine levels. These animals reacted to the homeopathically prepared thyroxine with a slowing down of metamorphosis, even when they had not been prestimulated with a molecular dose of the hormone. This effect was observed in all 3 laboratories and is consistent with the results of previous studies.

Animals↗
PubMed1968

Increased thyroxine turnover and thyroidal function after stimulation of hepatocellular binding of thyroxine by phenobarbital.

Administration of phenobarbital to rats in a dosage schedule previously demonstrated to increase hepatocellular binding of thyroxine results in increased hormonal turnover, due both to increased deiodination and to fecal disposition of thyroxine iodine. The rate of biliary excretion of thyroxine iodine is roughly proportional to the hepatic content of exchangeable thyroxine. The enhanced peripheral disposition of thyroxine appears to lead to increased thyroidal function, as measured by isotopic iodine studies, and the maintenance of a normal nonradioactive serum PBI. On the other hand, thyroidectomized animals maintained on a constant replacement dose of L-thyroxine and treated with phenobarbital exhibit a marked fall in serum PBI. These findings suggest that increased thyroxine flux in phenobarbital-treated animals is secondary to primary stimulation of hepatocellular binding. Exchangeable intracellular thyroxine may thus be an important determinant of hormone turnover and, possibly, of hormonal action.

Animals↗
PubMed1991

The determination of thyroxine and thyroxine uptake with new homogeneous enzyme immunoassays using Boehringer Mannheim/Hitachi analysis systems.

New homogeneous enzyme immunoassays for the determination of thyroxine and thyroxine uptake have been developed. The CEDIA assays are based on the cloned enzyme donor immunoassay technology, which involves fragments of beta-galactosidase prepared by genetic engineering. The assays have been adapted for Boehringer Mannheim/Hitachi analysers. The CEDIA T4/T Uptake assays were evaluated in eleven clinical chemistry laboratories on various Boehringer Mannheim/Hitachi analysis systems, using a 2-point calibration. The analytical range of the T4 test was 10 to 258 nmol/l thyroxine. The T uptake test had a measuring range between 20-50%. Depending on the concentration of the analyte (samples from hypo-, eu- or hyperthyroid patients), mean coefficients of variation ranged from 1.8 to 4.8% within-run and from 4.1 to 6.5% between-run for the T4 assay. Even better coefficients of variation were obtained for the T uptake assay (1.4 to 2.3% within-run, 2.8 to 3.3% between run). The relative inaccuracy of the CEDIA assays with respect to values assigned by other tests was satisfactory in various control sera. The T4 assay was compared with one radioimmunoassay, one enzyme immunoassay and one fluorescence polarisation immunoassay. Slopes ranging from 0.9 to 1.1 and intercepts ranging from -10 to +10 nmol/l thyroxine were obtained with two exceptions. The results of the T uptake test correlated reasonably with those of other thyroxine-binding methods. No interference was observed with icteric and lipaemic sera. Haemoglobin up to 4 g/l had no significant influence. Results of the CEDIA T Uptake test are mainly used for calculation of the free thyroxine index, in which the thyroxine value is corrected for variations of thyroxine-binding protein concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoanalysis↗
PubMed1983

Elevated thyroxine levels due to increased thyroxine-binding globulin in acute hepatitis.

Two patients are presented who had unexpected increases in serum thyroxine concentration due to acquired thyroxine-binding globulin excess associated with asymptomatic hepatitis. Serum hormone concentrations were also analyzed retrospectively in 10 outpatients with viral hepatitis. Acute hepatitis is associated with an increase in serum thyroxine and thyroxine-binding globulin concentrations and a corresponding decrease in the triiodothyronine resin uptake. In five patients, serum thyroxine concentration (mean +/- SD) was elevated at 21.08 +/- 5.86 micrograms/dl during illness, and decreased to 10.18 +/- 2.96 micrograms/dl during full recovery (p less than 0.05); serum thyroxine-binding globulin concentration was elevated at 2.14 +/- 0.36 mg/dl during illness, and decreased to 1.18 +/- 0.16 mg/dl during recovery (p less than 0.01). Interpretation of thyroid function test results can be difficult in patients with hepatitis. When serum thyroxine is elevated, careful attention to a decrease in the triiodothyronine resin uptake is essential to avoid the incorrect diagnosis of hyperthyroidism. Occasionally, this change in the triiodothyronine resin uptake may be the first evidence of occult hepatic inflammation.

Acute Disease↗
PubMed1983

Effect of albumin concentration on the assay of serum free thyroxin by equilibrium radioimmunoassay with labeled thyroxin analog (Amerlex Free T4).

Serum free thyroxin (FT4) in normal nonpregnant and pregnant subjects was measured by radioimmunoassay (RIA) with Amerlex FT4 RIA (Amersham International) and LiquiSol FT4 RIA (Damon Diagnostics) kits. Amerlex FT4 values in serum from pregnant women were lower than those in serum from nonpregnant women, but LiquiSol FT4 values were similar in serum from both groups. Amerlex FT4 values were directly correlated with the concentrations of albumin in serum and inversely correlated with those of thyroxin-binding globulin, but not with prealbumin concentrations. No significant correlations were observed between LiquiSol FT4 values and serum concentrations of thyroxin-binding proteins. Amerlex FT4 values were normal in patients with excess, deficient, or decreased thyroxin-binding globulin. Albumin added to serum samples increased Amerlex FT4 values but not LiquiSol FT4 values. Albumin inhibited the binding of labeled thyroxin analog to the solid-phase thyroxin antibody. These data indicate that the albumin concentration influences FT4 values as measured by an RIA involving a thyroxin analog and that Amerlex FT4 values should be carefully interpreted when the patient has an abnormal concentration of serum albumin.

Female↗
PubMed1985

'Chemical hyperthyroidism': the significance of elevated serum thyroxine levels in L-thyroxine treated individuals.

We have previously reported that L-thyroxine treated patients may often have elevated serum T4 concentrations and yet show no clinical signs of hyperthyroidism. We found that such patients had normal serum T3 concentrations. The present study explored the relationship between serum T3 and T4 and dosage of L-thyroxine. Retrospective analysis of 99 patient records was performed. There was an increase of serum T4, serum T3 resin uptake (T3R), and T3 with increasing dose of L-thyroxine. The T3/T4 ratio decreased with increasing dose of L-thyroxine and with increasing T4. This phenomenon was analysed prospectively by starting 23 individuals on L-thyroxine and progressively incrementing the dose until either symptoms of hyperthyroidism developed or T4 levels exceeded the upper unit of the normal range. Once again, there was a progressive increase in serum T4, T3R, and T3 with increasing dose of L-thyroxine. At even the lowest dose of L-thyroxine (0.05 mg), there was a marked fall in T3/T4 ratio as compared to untreated individuals. The T3/T4 ratio fell further with increasing dose but with a fairly weak correlation. The decrease in T3/T4 ratio showed a much stronger correlation with serum T4. Of the 23 individuals, all exceeded the upper limit of the normal range of serum T4. No individual with elevated T4 developed clinical signs of hyperthyroidism unless serum T3 was also elevated beyond the normal range. Of eight individuals who reached elevated T3 levels, six demonstrated clinical signs of hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1992

Plasma total thyroxine and free thyroxine concentrations in congenital hypothyroidism before and during treatment.

AIMS: To examine the relation between plasma total thyroxine and free thyroxine in children with congenital hypothyroidism. METHODS: Regression analysis was performed on 114 cases on the paired total thyroxine and free thyroxine measurements taken from the same blood sample. Conversion equations were derived using structural relation models. RESULTS: A linear relation was found between log total thyroxine and log free thyroxine values. The regression slopes for values taken before treatment and values taken while patients were receiving replacement treatment were significantly different. CONCLUSIONS: The data suggest that there is a close association between total and free thyroxine in congenital hypothyroidism, but that the relation is changed by thyroid replacement treatment.

Congenital Hypothyroidism↗