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  • Author: Carsten Kirkegaard x
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Carsten Kirkegaard and Jens Faber

Abstract.

Total and free concentrations of T4 and rT3 in serum and cerebrospinal fluid were estimated by ultrafiltration in 12 patients with unipolar endogenous depression before and after electroconvulsive treatment. Recovery from depression resulted in a decrease in CSF concentrations of free T4 (median) (26.2 to 21.4 pmol/l, p<0.02) and free rT3 (14.1 to 12.3 pmol/l, p<0.05). Concentrations of free T4 in the cerebrospinal fluid were lower than those in serum (p<0.02), the ratio being 0.6. In contrast, levels of free rT3 in the cerebrospinal fluid were considerably higher than those found in serum (p<0.01), the ratio being 25. These ratios did not change following recovery from depression. In 9 patients with nonthyroidal somatic illness, concentrations of free T4 and rT3 in the cerebrospinal fluid were similar to those found in patients with endogenous depression, whereas 4 hypothyroid patients and one hyperthyroid patient had considerably lower and higher, respectively, concentrations of both free T4 and rT3. In conclusion, levels of free T4 and free rT3 in the cerebrospinal fluid are increased during depression compared with levels after recovery, probably reflecting an increased supply of T4 from serum and an increased production of rT3 from T4 in the brain. The data also suggest that the transport of iodothyronines between serum and the cerebrospinal fluid is restricted.

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Jens Faber, Kaj Siersbæk-Nielsen and Carsten Kirkegaard

Abstract. The 24-h urinary excretion and renal clearance of thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), 3,3'-diiodothyronine (3,3'-T2), and 3',5'-diiodothyronine (3',5'-T2) were measured in 17 healthy subjects. The median urinary excretion was (pmol/24h) T4: 1242, T3: 828, rT3: 12.9, 3,3'-T2: 331, and 3',5'-T2: 5.8. The corresponding renal clearances were in median (ml/min) T4: 31, T3: 133, rT3: 15, 3,3'-T2: 683, and 3',5'-T2: 4.5. The clearances differed mutually (P < 0.01) as well as from the creatinine clearance (P < 0.01) which was in median 87 ml/min. Thus, all iodothyronines studied were subject to tubular transport mechanisms besides glomerular filtration. The 3 iodothyronines with 2 iodine atoms in the phenolic ring of the thyronine molecule, T4, rT3 and 3',5'-T2, were mainly tubularly reabsorbed, whereas those with only one iodine atom in the phenolic ring, T3 and 3,3'-T2, were mainly tubularly secreted. It might be hypothesized that the number of iodine atoms in the phenolic ring determines the direction of the tubular transport (presence of 2 iodine atoms is associated with tubular reabsorption, and of one iodine atom with secretion), whereas the rate of tubular transport decreases with decreasing number of iodine atoms in the tyrosylic ring.

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Carsten Kirkegaard, Jens Faber, Kaj Siersbæk-Nielsen and Thorkild Friis

Abstract.

A radioimmunoassay (RIA) for serum 3,5-diiodothyronine (3,5-T2) was developed using small Sephadex G 25 (fine) columns. Prior to the RIA an alcohol extraction of 3,5-T2 from serum and an evaporation of the extract was performed. The recovery of 3,5-T2 added to serum was in mean (± sem) 101 ± 11%. The lower detection limit was 0.012 pmol/column corresponding to 14 pmol/l using 3 ml serum. Due to a 5% cross-reaction of the 3,5-T2 antibody with 3,5,3'-triiodothyronine (T3) individual correction for T3 present in serum was necessary. Serum 3,5-T2 levels in 52 éuthyroid controls were (mean ± SD) 105 ± 51 pmol/l. Serum levels were higher in men (125 ± 56 pmol/l) than in women (84 ± 34 pmol/ l, P < 0.005). In 17 hyperthyroid subjects serum 3,5-T2 levels were elevated (232 ± 187 pmol/l, P < 0.005). In hypothyroid patients and patients with non-toxic goitre serum 3,5-T2 levels did not differ significantly from control values, whereas 8 patients with liver cirrhosis had severely reduced serum 3,5-T2 concentrations (20 ± 23 pmol/l, P < 0.001).

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Henning Bliddal, Carsten Kirkegaard, Kaj Siersbæk-Nielsen and Thorkild Friis

Abstract.

Thyrotrophin binding inhibiting immunoglobulins (TBII) were measured in 27 patients with Graves' disease during and after longterm antithyroid treatment. The median observation period after treatment was 24 months. During the first 6 months of treatment the TBII index increased significantly in both the relapse and the remission group, but during the rest of the treatment and the observation no further change was observed. Patients with a TBII index below 0.35 at drug withdrawal (n = 8) all relapsed and patients with values above 1.00 (n = 5) all stayed in remission. There was a significant correlation between the TBII index at drug withdrawal and the time elapsed before a relapse. Graves' disease was treated with 131I in combination with carbimazole in 22 patients. The TBII index of these patients decreased after 131I and increased towards normal values during longterm observation of median 33 months. Of 4 patients with euthyroid ophthalmopathy one was TBII positive. This patient became overt hyperthyroid after an observation period of two years of prednisone treatment. It is concluded, that the TBII index is of some prognostic value after longterm antithyroid treatment, but is of no clinical importance following 131I treatment.

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Jens Faber, Carsten Kirkegaard, Bo Jørgensen and Jørgen Kludt

Abstract. The validity of estimation of the production rates of T3 and rT3 in man based on noncompartmental analysis of blood-derived data has been questioned owing to incomplete exchangeability of T3 and rT3 between plasma and extrathyroidal tissues in which a local production of these iodothyronines takes place. The possible existence of a nonexchangeable or hidden pool of T3 and rT3 would result in an underestimation of the daily production. By contrast, the production rate of T4 can be estimated reliably using noncompartmental analysis. We have studied 16 women with pretreatment severe hypothyroidism on constant levothyroxine therapy. Simultaneous measurements of T4, T3 and rT3 production rates were performed using bolus injection of radiolabelled iodothyronines. The tracers were isolated from plasma using gel separation/antibody extraction, and production rates were calculated by noncompartmental analysis. Mean (± sd) production rate of T4, T3 and rT3 were: 119 ± 43, 40.0 ± 22.0 and 54.9 ± 20.0 nmol · day−1 · (70 kg)−1, respectively. Thus 79.5 ± 7.0% of T4 was deiodinated into T3 and rT3. This leaves 20.5% to other metabolic pathways of T4 and to a possible underestimation of T3 and rT3 production rate. Based on conservative estimates from the literature, the other metabolic pathways of T4 amount: oxidative deamination 1.1%; ether link cleavage 0%; urinary excretion 2.5%; and fecal excretion 14%. Thus, the various metabolic pathways seem to explain 97% of daily produced and degradated T4 in man. Therefore the understimation of T3 and rT3 production rates in man using noncompartmental analysis seems of little if any importance, and existence of a hidden pool of these iodothyronines may be questioned.

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Ulrik Birk Lauridsen, Carsten Kirkegaard, Thorkild Friis and Kaj Siersbæk-Nielsen

ABSTRACT

During antithyroid treatment a total of 88 TRH tests was performed in 56 clinical euthyroid patients. 56 % had negative response to TRH (i. e. Δ TSH < 2 μU/ml) after being treated in average 12.6 months and no relation between the duration of treatment and the outcome of the TRH test was found. In the group with positive TRH tests (i. e. Δ TSH > 2 μU/ml) the mean T4 value was slightly decreased (5.8 ± sd 2.5 μg/100 ml) while the mean T3 value was normal (121 ± sd 32 ng/100 ml). The group with negative TRH tests had quite normal serum T4 values (9.3 ± sd 3.1μg/100 ml) but in general high normal or elevated serum T3 values (175 ± sd 31 ng/100 ml). Our results seem to indicate that serum T3 is of greater importance than serum T4 with regard to the outcome of the TRH test. The majority of the cases with negative TRH tests, however, had serum T3 and T4 values within normal range. In almost all patients with a negative TRH test a negative T3 suppression of 131I uptake in the thyroid gland was found while a positive TRH test was not correlated with suppressibility of 131I uptake.

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Jens Faber, Thorkild Friis, Carsten Kirkegaard and Kaj Siersbæk-Nielsen

ABSTRACT

A simple radioimmunoassay for serum reverse triiodothyronine on small reusable Sephadex G 25 fine columns has been developed. The assay was unaffected by serum volumes of up to 100 μl. The recovery of reverse T3 added to serum was in the mean 98.3 ± sem 3.2 % and the coefficient of variation within and between assay determinations 5.4 % and 7.5 %, respectively. The detection limit was 2.2 pg reverse T3/column. Serum reverse T3 in 58 euthyroid controls was in mean 48 ± sd 9 ng/100 ml, and was positively correlated to age (P < 0.001). No overlap was found between the control group, and the hypo- and hyperthyroid group respectively. Three patients with T3-toxicosis had a normal serum rT3.

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Jens Faber, Sven Poulsen, Per Iversen and Carsten Kirkegaard

Abstract. Patients with small cell carcinoma of the lung often present with symptoms suggestive of hyperthyroidism i.e. weight loss without anorexia. Consequently [125I]T4 and [131I]T3 turnover was studied using simultaneously iv bolus injection and noncompartmental analysis in 6 patients with untreated small cell carcinoma of the lung and 14 normal subjects of comparable ages. Both T4 and T3 production rates were enhanced, T4 production being in median 135 nmol · day−1 · 70 kg−1 (range 111–200) in patients with small cell carcinoma of the lung vs 98 nmol·day−1 ·70 kg−1 (range 69–134) in controls (P < 0.01), and T3 production being 46 nmol · day−1·70 kg−1 (range 33–65) vs 31 nmol ·day−1 ·70 kg−1 (range 24–45) (P < 0.01). The mean transit time was shortened for both T4 and T3, T4 mean transit time being 5.9 days (3.9–8.0 days) vs 8.3 days (6.1–11.2 days) in controls (P < 0.01), and T3 mean transit time being 0.74 days (0.36–0.98 days) vs 1.03 days (0.81–1.45 days) in controls (P < 0.01). Serum total and free T4 and T3 levels were unchanged. Basal serum TSH levels and the TSH response to iv TRH were also normal. Thyroid-stimulating immunoglobulins were only present in the serum in 1 of 6 patients. Thus, thyroid hormone production seemed under pituitary regulation. The peripheral effect of thyroid hormones was evaluated measuring serum sex hormone binding globulin levels, which were increased to in median 270% (77–310%) (P < 0.01) of that in controls, suggesting some degree of hyperthyroidism in liver tissue. One patient was re-investigated after complete remission, which resulted in normalization of T4 and T3 production and mean transit time, as well as serum sex hormone binding globulin levels. The data demonstrate that patients with untreated small cell carcinoma of the lung have enhanced turnover of thyroid hormones, a pattern quite different from that usually seen in non-thyroidal somatic illness.

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Jens Faber, Carsten Kirkegaard, Ib Bo Lumholtz, Kaj Siersbæk-Nielsen and Thorkild Friis

Abstract.

Serum levels of thyroxine, 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), 3,3'-diiodothyronine (3,3'-T2), 3',5'-diiodothyronine (3',5'-T2) and TSH were measured in two clinical situations which are both known to induce a low serum T3 high serum rT3 syndrome: 1) during the early course of acute myocardial infarction (AMI) and after recovery, and 2) before and during one week's propranolol medication (20 mg 4 times a day). In 10 patients with AMI serum levels of the iodothyronines were unchanged on admission to hospital (in average 6.6 h after onset of symptoms). However, already 24 h after onset of symptoms serum T3 and 3,3'T2 were reduced whereas serum rT3 and 3',5'-T2 were increased. Serum T3 and 3,3'-T2 reached a nadir on day 4 and 3, respectively, whereas serum rT3 and 3',5'-T2 reached peak values 24 h after onset of symptoms.

In eight healthy, euthyroid volunteers propranolol medication induced similar changes in iodothyronine concentration as AMI did. However, the alterations were more delayed. Serum T3 decreased slowly reaching statistically significantly reduced values on day 7. Serum rT3 and 3',5'-T2 were significantly enhanced from day 3 and 4, respectively. A close parallelism in alterations of serum T3 and 3,3'-T2 levels was observed.

Our data suggest that T3 in the two situations studied is a major precursor for 3,3'-T2 probably as a consequence of reduced 5'-deiodinase activity. It seems possible that the mechanisms affecting the metabolism of the iodothyronines in AMI and during propranolol medication involved the same enzyme system. However, the late appearance of the alterations in serum iodothyronines levels during propranolol medication might indicate different modes of action.

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Jens Faber, Thorkild Friis, Carsten Kirkegaard, Ulrik Birk Lauridsen, Jørn Nerup, Preben Rogowski and Kaj Siersbœk-Nielsen

ABSTRACT

Fifty-five normal subjects were studied following intravenous injection of increasing doses of bovine thyrotrophin (b-TSH) from 0.5 to 250 mU/kg. Serum triiodothyronine (T3) and thyroxine (T4) were measured 1, 2, 3 and 4 h after the TSH injection. Dose-related increments in serum T3 and T4 were demonstrated with doses of b-TSH = 2.5 mU/kg and a maximum response was obtained after approximately 100 mU/kg. The fractional increase in serum T3 was greater than in serum T4, but the ratio between the increase in serum T4 and serum T3 (21.3/1 ng/ng) was independent of the dose of b-TSH and time after TSH stimulation. The T3 response was reproducible and unaffected by sex and age.