[False results on elevated triiodothyronine values in radioimmunoassay]. / Falsk forhøjelse af trijodtyroninvaerdier ved radioimmunanalyse.

Five patients with falsely elevated serum triiodothyronine (T3) concentrations (> 9 nmol/l) in a radioimmunoassay are reported. The high T3-values disagreed with the other thyroid variables investigated as well as with the clinical observations. In sera from all patients a normal non-specific binding of T3 was found, thus excluding abnormal serum-protein-binding of the hormone. An ethanol extraction of T3 from serum before RIA reduced the T3 content in serum from all patients to normal levels (2.0-2.4 nmol/l). These findings indicate the presence in the sera of substances, probably of protein nature, that were interfering with the assay by binding the reagent-antibody and not the antigen. Addition of non-immune rabbit serum prevented this interference and normalized the T3-values (1.8-2.4 nmol/l). Thus the interfering substance in T3-RIA could be an anti-rabbit antibody, the interaction of which can be eliminated by a minor modification of the assay making it possible to differentiate true from false T3-values.

The thyroid function and size in healthy man during 3 weeks treatment with beta-adrenoceptor-antagonists.

The influence of beta-adrenoceptor antagonists on serum TSH level (supersensitive method) and thyroid volume has not previously been studied. Thirty-two young non-smoking males were treated for 3 weeks with either atenolol 50 mg (b.i.d.), metoprolol 100 mg (b.i.d.) or propranolol 80 mg (b.i.d.) in a placebo controlled study. After 1 week, median serum TSH level increased in the atenolol (from 1.76 (range: 0.96-4.04) to 2.25 (range: 1.11-4.22) mU/l, P less than 0.05) and propranolol (from 1.91 (range: 0.90-3.83) to 2.44 (range: 0.75-6.30) mU/l, P less than 0.05) treated groups. After 3 weeks, median serum TSH reached pretreatment level in the atenolol treated, whereas median serum TSH decreased compared to pretreatment values in the propranolol treated (1.68 (range: 0.68-3.62) mU/l, P less than 0.05). Except for a slight increase in the atenolol treated group, no changes in median thyroid volume was seen after 3 weeks. The changes in serum TSH or thyroid volume were not related to changes in the concentrations of thyroid hormones, or of a magnitude likely to interfere with the clinical evaluation of thyroid function.

Acute beta-blockade changes the extracellular distribution of thyroid hormones.

The acute (within hours) changes in the concentrations of T4, T3, reverse-T3 (rT3) and T3 resin uptake test (T3RU) were studied in 31 hyperthyroid patients for 4 h after po treatment with either acebutolol, oxprenolol, pindolol or timolol. In 21 of the patients, the changes were compared to changes in the serum concentrations of alpha 2-macroglobulin (a macromolecule) and two middle-sized molecules; thyroid hormone-binding globulin (TBG) and albumin in order to calculate the changes in extracellular distribution of the thyroid hormones and to distinguish between changes due to a changed metabolism and changes due to a changed distribution of the thyroid hormones. Acebutolol, oxprenolol and timolol caused a decrease in serum T3 after 1/2 h, and acebutolol and oxprenolol also a decrease in rT3 after 1/2 - 1 h, the changes reversed within 2 h. A concomitant decrease in serum albumin and TBG suggests a change in the extracellular distribution of middle-sized molecules to which thyroid hormones are attached, as an explanation of the acute decrease (1 h) of the thyroid hormones. The small and insignificant change in alpha 2-macroglobulin indicates that the changes are mainly extravascular, but the difference of alpha 2-macroglobulin changes between the drugs (acebutolol/timolol vs pindolol/oxprenolol) could depend on the intrinsic sympathomimetic activity of the drugs.

Differential effect of continuous administration of beta-adrenoceptor antagonists on antipyrine and phenytoin clearance.

1. Antipyrine (1000 mg orally) clearance was studied 3 days before treatment with either atenolol (50 mg twice daily), metoprolol (100 mg twice daily), propranolol (80 mg twice daily) or placebo, and at day 5 and 18 during treatment. Phenytoin (100 mg intravenously) clearance was measured on days 0, 7 and 21 during treatment. 2. Antipyrine clearance was decreased by about 20% after 5 days of treatment with either propranolol or atenolol and this decrease persisted after 18 days of treatment. Antipyrine clearance did not change during treatment with either metoprolol or placebo. Phenytoin clearance did not change during any of the treatments.

Influence of rifampicin and isoniazid on the kinetics of phenytoin.

Clearance of phenytoin after i.v. injection of 100 mg was studied in six patients before and after 2 weeks daily treatment with 450 mg rifampicin, and in 14 patients with tuberculosis receiving standard treatment with 450 mg rifampicin, 300 mg isoniazid, and 1200 mg ethambutol daily. Acetylator status was measured by urinary acetylated sulphadimidine. Clearance of phenytoin in patients receiving only rifampicin increased from 46.7 ml min-1 +/- 20.6 ml min-1 to 97.8 ml min-1 +/- 33.4 ml min-1 (P less than 0.01), while clearance in patients on three drugs increased from 47.1 +/- 23.4 ml min-1 to 81.3 ml min-1 +/- 41.6 ml min-1 (P less than 0.01). No significant differences were observed between the six fast acetylators and the eight slow acetylators. Phenytoin kinetics were unchanged after further 3 months of combined treatment. Rifampicin is a strong inducer of the elimination of phenytoin. Combined treatment with isoniazid has no counter-acting effect in either fast or slow acetylators.

High frequency of goitre in cigarette smokers.

Thyroid function, the clinical occurrence of goitre and ultrasonically determined thyroid gland volume were investigated in 219 healthy subjects randomly chosen from hospital employees. Thirty-five subjects (16%) had a clinically detectable goitre. The frequency of goitre among smokers was higher (32 of 107, 30%) than among non-smokers (3 of 112, 3%), (P less than 0.001). Median thyroid volume was significantly higher in smokers, 26 ml (range 11-55 ml), compared with non-smokers, 15 ml (range 8-37 ml), (P less than 0.001). The median serum thyroglobulin levels were significantly higher and median serum thyrotropin levels lower in smokers compared with non-smokers. There were no differences between the groups regarding serum levels of T4, T3, rT3, free T4 index, free T3 index, thyroglobulin antibodies and 131I uptake (24 h) in the thyroid gland. It is suggested that these findings could partly be due to inhaled thiocyanate and/or increased adrenergic stimulation of the thyroid gland in smokers.

Long-term alprenolol treatment affects serum T4, T3 and rT3 in euthyroid patients with ischaemic heart disease.

After treatment with alprenolol for 1 year, serum 3,3',5'-triiodothyronine (rT3) was significantly increased (P less than 0.01) in a group (n = 20) of euthyroid subjects compared to a control group (n = 20) given placebo. All subjects had definite or suspected myocardial infarction one year previously. Serum thyroxine (T4), free T3 index (FT4I), serum 3,5,3'-triiodothyronine, (T3) and free T3 index (FT3I) were not significantly different in the two groups. Alprenolol and placebo were gradually withdrawn over 14 days. On the first day after withdrawal a significant decrease in serum rT3 in the alprenolol treated group was the only change observed. Fourteen days after withdrawal a significant fall in serum T4, FT4I, rT3 and a rise in serum T3 and FT3I was found in the alprenolol treated group. Six months after withdrawal the only further change observed in the alprenolol treated group was an increase in T3 and FT3I. No changes occurred in the placebo treated group in any of the hormones studied. The results are consistent with a direct effect of long-term alprenolol treatment on the peripheral levels of serum T4, T3 and rT3 in euthyroid subjects. The changes in the thyroid hormones after withdrawal further indicate withdrawal of a permanent inhibition of 5'deiodinase during long-term treatment with alprenolol in euthyroid subjects.

"Low T3-syndrome" in acute myocardial infarction--relationship to beta-adrenergic blockade and clinical course.

Serum levels of T4, T3 rT3 and resin T3 uptake were followed for 5 days in 40 patients with acute myocardial infarction (AMI) allocated to early treatment either with alprenolol or placebo. There was a significant fall in T3 (P less than 0.05) and an increase in rT3 (P less than 0.05) without any significant difference between the alprenolol - (n = 19) and placebo - (n = 21) treated groups. The risk of missing a further 20% change in se-T3 and se-rT3 after alprenolol compared to placebo treatment (beta) was less than 0.10 and less than 0.50, respectively. In patients with a severe clinical course, the fall in T3 and increase in rT3 was significantly greater than in patients without complications. No change in T4 was observed either with respect to the clinical course nor following alprenolol. The data suggest that alprenolol can be given in the acute phase of myocardial infarction without causing any additional disturbance in the serum levels of T3 and T4.

Different effects of propranolol, alprenolol, sotalol, atenolol and metoprolol on serum T3 and serum rT3 in hyperthyroidism.

Serum T4, T3, rT3 and T3 resin uptake (T3 RU) were measured before and after 7 days of treatment with either propranolol, alprenolol, sotalol, atenolol or metoprolol in hyperthyroid patients. We found a significant decrease in serum T3 after propranolol, alprenolol, atenolol and metoprolol but no change in the sotalol treated group. A significant increase in rT3 was found in the propranolol and alprenolol treated groups whereas a significant fall in rT3 was found in the atenolol and metoprolol treated groups. No change was found in the sotalol treated group. The changes observed in serum T3 and in rT3 could be explained by an inhibition of the 5'deiodinase enzyme by propranolol and alprenolol and an inhibition of both the 5'deiodinase and 5 deiodinase enzymes caused by atenolol and metoprolol.

Beta 2-adrenoceptor agonists and thyroid hormones.

The potential influence of the selective beta 2-adrenoceptor agonist terbutaline on the serum concentration of the thyroid hormones in humans was studied in 11 healthy euthyroid subjects. Five served as a control group without medication while six received 5 mg terbutaline three times daily for 2 weeks. No significant differences were found between the two groups by measuring the serum concentrations of thyroxine, triiodothyronine, reverse triiodothyronine and resin-triiodothyronine uptake. The use of a beta 2-adrenergic receptor stimulating drug is relatively contraindicated in untreated thyrotoxicosis. This recommendation is based upon a summation of clinical adverse reactions and not due to an effect on the serum concentrations of thyroid hormones.

Disposition of antipyrine and phenytoin correlated with age and liver volume in man.

The half-life and metabolic clearance rate (MCR) of antipyrine and phenytoin were determined in 14 young (mean age: 28.8 +/- 8.3 (SD) years] and in 14 elderly [mean age: 83.5 +/- 7.1 (SD) years] subjects and correlated with liver volume, which was determined by ultrasonic scanning, to see if an age-dependent difference in drug metabolism could be explained by a reduced liver weight with age. The size of the liver was smaller in the elderly subjects even when related to decreased body surface. A significant decrease in serum albumin in the elderly compared with the younger group was also noted. The half-life of antipyrine was significantly longer in the elderly than in the younger group, 756 +/- 318 and 465 +/- 110 minutes, respectively, and the MCR was correspondingly lower in the elderly even when calculated per litre of live volume, 22.8 +/- 7.8 and 36.3 +/- 8.9ml/minute/L liver volume, respectively. No significant differences in the 2 age groups were found in half-life and total clearance of phenytoin, but a reduced free phenytoin clearance was demonstrated in the elderly (240 +/- 92ml/minute/L liver volume) compared with the younger (325 +/- 81ml/minute/L liver volume) group. No significant correlation was found between liver volume and the half-life of antipyrine and phenytoin. However, a significant correlation was demonstrated between liver volume and MCR of antipyrine as well as between total and free clearance of phenytoin. No correlation was found between the half-lives of the 2 drugs, while a significant correlation existed between the clearance values. It is suggested that the age-dependent reduction in drug clearance is due not only to a smaller liver volume, but it also a result of a reduced capacity of the liver microsomes per unit of liver in the elderly. With regard to age-dependent changes in drug metabolism, the protein binding of the actual drug has to be taken into consideration.

Iodothyronines and thyrotrophin in serum after jejunoileostomy with 3:1 or 1:3 jejunoileal ratio.

Serum levels of thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3) and thyrotrophin, and T3-uptake were measured in 13 morbidly obese patients preoperatively and during the first five months after jejunoileal bypass surgery, in which period the patients lost 20% in body weight. They were randomized to a ratio of 3:1 or 1:3 between the jejunal and ileal segment included in the bypass, but the results in the two groups did not differ significantly. T4 level showed a slight decrease during the five months after surgery. T3 level was reduced to 82% of the preoperative value within the first month of surgery, and was stable thereafter. rT3 level was unaffected by surgery, as was the level of thyrotrophin. T3-uptake increased slightly after surgery. These findings are compatible with caloric restriction with low carbohydrate intake, and suggests that disruption of the enterohepatic circulation of iodothyronines is without clinical importance.

Incomplete separation of radioiodinated thyroid hormones in serum using specific antibodies.

Alkaline Sephadex G-25 columns were used to separate labelled 3,5,3',5'-thyroxine, 3,5,3'-triiodothyronine, 3,3',5'-triiodothyronine and 3,3'-diiodothyronine from the serum binding proteins followed by a quantitative elution of each hormone by coupling to its respective antibody. It is shown that although these antibodies (diluted 1:1500-1:100 000) in our radioimmunoassays are highly specific they show a high degree of non-specific binding when they are used in the concentrations necessary to get a maximal recovery of the hormones in column separating experiments.

Influence of age on the endocrine-metabolic response to surgery.

The pathogenesis of the increased operative risk in elderly patients is unknown. From a theoretical point of view, a change in endocrine-metabolic response might be involved. In the present study, a battery of hormonal and metabolic variables were measured in eight young and eight elderly healthy males undergoing elective inguinal hernial repair under general anesthesia. Blood was drawn before induction of anesthesia, at skin incision, and one, two, and six hours after skin incision. The findings were: 1) Plasma cortisol increase was significantly higher in elderly than in young controls. 2) Plasma renin level was lower in old age, but renin-aldosterone and electrolyte response patterns were alike in the two groups. 3) Thyroid parameters, in terms of serum T4, serum T3, serum rT3, and T3-resin uptake, responded normally to surgery and showed no age-related differences. 4) The hyperglycemic response was not significantly influenced by age indicating unchanged glycoregulatory mechanisms also verified by determinations of plasma catecholamines, cAMP, and insulin. 5) Blood lymphocyte count was constantly lower in elderly than in young and decreased with time, but the age-related difference was not significant. 6) Blood polymorphonuclear leukocytes showed an increase of the same magnitude in both age groups, although at a significantly slower rate in the elderly. It is concluded that age affects some aspects of the initial endocrine-metabolic response to surgery.

Effect of exercise on thyroid parameters and on metabolic clearance rate of antipyrine in man.

UNLABELLED: Serum concentrations of thyroxine, triiodothyronine, free-thyroxine-index, free-triiodothyronine-index and reverse-triiodothyronine (r-T3) were followed in nine normal men, aged 18 to 22 years, during a nights rest and during nine hours march (4.6 km/h). In addition antipyrine elimination was measured in the same periods after iv injection of 1 gram of antipyrine. No significant differences were found in any of the thyroid parameters during exercise except for a small increase in serum r-T3 after 3 hours. During rest a small but significant decrease was found in serum r-T3. Otherwise no significant differences were found except for a significant increase in free-T3-index after 3 hours rest. The mean value of total body clearance of antipyrine was identical at rest and during exercise. IN CONCLUSION: Prolonged exercise does not change the metabolic clearance rate of antipyrine and does not elicit any major change in the serum concentrations of the thyroid hormones.

Abnormal gamma globulin binding of thyroid hormones.

Thyroid hormone levels were studied in a thyrotoxic patient, who was treated with propylthiouracil. He had heavily increased triiodothyronine concentrations, measured by radioimmunoassay, in spite of only mild clinical symptoms of thyrotoxicosis. A moderately increased serum triiodothyronine concentration was observed in another patient, who was euthyroid and who had recently recovered from subacute thyroiditis. By gel electrophoresis and precipitation tests with human anti-IgG and anti-IgA, a binding to the gamma globulins of both triiodothyronine and thyroxine was detected in patient 1, and of triiodothyronine in patient 2. Such abnormal binding may result in serious errors in the determination of thyroid hormone concentration by radioimmunoassay.

Radioimmunoassays of T3, r-T3 and r-T'2 in human serum.

Simple radioimmunoassays for 3,3',5-triiodothyronine (T3), 3,3',5'-reverse-triiodothyronine (r-T3) and 3,3'-diiodothyronine (r-T'2) in human serum are described. The princple of the methods is the same and based on a system using 8-anilino-1-naphthalene sulfonic acid as an inhibitor of nonspecific protein binding, a simultaneous addition of the antibody and the labelled hormone, an overnight incubation at room temperature and a separation of bound and free hormone with dextran-coated charcoal. The methods require 15 microliter, 50 microliter and 100 microliter (or 333 microliter for ethanol extraction) serum respectively. Serum concentrations (mean +/- SD) of T3, r-T3 and r-T'2 from normal subjects are 144 +/- 19 ng T3/100 ml (n = 52), 32 +/- 7 ng r-T3/100 ml (n = 36), 3.8 +/- 0.7 ng r-T'2/100 ml (ethanol extraction, n = 18) and 8.2 +/- 1.6 ng r-T'2/100 ml (unextracted, n = 16).