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Laszlo Hegedüs and Jens Faber

Radioactive iodine (131I) has been used for half a century and proved effective in treating hyperthyroidism. It is safe, cheap and relatively free from side effects. Iodine-131 is used in most cases of nodular toxic goitre and regarded as the treatment of choice for patients with Graves' disease who do not remit following a course of antithyroid drugs (1, 2). Although large surveys among European (3) and American (4) thyroidologists have disclosed some differences in attitude, this treatment is increasingly used. In fact, many thyroidologists have come to the conclusion that antithyroid drugs aiming at inducing remission of the hyperthyroidism should be reserved for young patients and those with normal or only slightly increased thyroid size. In Denmark this would limit the use of antithyroid drugs—for the purpose of inducing remission—to not more than 25% of the patients with hyperthyroidism (5, 6).

Recently, renewed interest in the treatment of

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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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Steen Jædig and Jens Faber

Abstract.

The effect of complete fasting on the serum concentrations of the iodothyronines 3,5-diiodothyronine (3,5-T2), 3,3'-T2, 3', 5'-T2 and 3'-monoiodothyronine (3'-T1) was evaluated. Fourteen obese women underwent a complete fasting for 4 days. Caloric restriction resulted in the following serum hormone levels (before vs 3. day): T4: 103 vs 109 nmol/l (NS), T3: 1.83 vs 1.24 nmol/1 (P < 0.01), rT3: 0.276 vs 0.407 nmol/l (P < 0.01), 3.5-T2: 70 vs 70 pmol/l (NS), 3.3'-T2: 42 vs 39 pmol/l (P < 0.01), 3',5'-T2: 63 vs 93 pmol/l (P < 0.01), and 3'-T1 60 vs 116 pmol/l (P < 0.01). All subjects were refed with 200 g (800 kcal, 3350 kJ) d-glucose per day in divided doses for 2 days. Refeeding tended to normalize the changed iodothyronine concentrations and there was no difference whether the glucose was administered by the oral (n = 7) or the intravenous route.

It can be concluded that starvation in man is accompanied by profound changes in peripheral metabolism of the T2's and 3'-T1. There seems to be no qualitative difference of the effect on the thyroid hormone metabolism of d-glucose administered by the oral or the intravenous route.

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Jens Faber and Anders Michael Galløe

Faber J, Galløe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to l-thyroxine treatment: a meta-analysis. Eur J Endocrinol 1994;130:350–6. ISSN 0804–4643

l-Thyroxine (l-T4) in the treatment of thyroid disease resulting in reduced serum thyrotropin (TSH) has been associated with reduced bone mass and thus the potential risk of premature development of osteoporosis. However, several recent studies have failed to show such a detrimental effect. These disagreements are probably due to only a small number of patients taking part in each study, decreasing the change of finding significant differences and increasing the risk of missing a real difference (type 1 and 2 errors, respectively). We therefore performed a meta-analysis on the available papers (N = 13), in which bone mass was measured in the distal forearm, femoral neck or lumbar spine in a cross-sectional manner in women with suppressed serum TSH due to l-T4 treatment and in a control group. The women were divided according to their pre- and postmenopausal state, because preserved estrogen production plays a protective role against irreversible bone loss. Based on the number of measurements performed on the different sites of the skeleton, a theoretical bone composed of 30.4% distal forearm, 28.8% femoral neck and 40.8% lumbar spine could be constructed in premenopausal women (441 measurements). A premenopausal woman at an average age of 39.6 years and treated with 164 μg l-T4/day for 8.5 years, leading to suppressed serum TSH, had 2.67% less bone mass than controls (NS), corresponding to an excess annual bone loss of 0.31% after 8.5 years of treatment (NS). The risk of not detecting an excess bone loss of at least 1% per year (type 2 error) was p < 0.15. Similarly, a postmenopausal woman with a bone consisting of 11.3% distal forearm, 42.0% femoral neck and 46.7% lumbar spine (317 measurements) at an average age of 61.2 years and treated with 171 μg l-T4/day for 9.9 years had 9.02% less bone mass than controls (2p < 0.007), corresponding to a significant excess of annual loss of 0.91% after 9.9 years of treatment. Eighteen papers with a mean of 18 patients showing no difference between postmenopausal patients and controls would have to be published or found before this difference could turn into a non-significant finding (the file drawer problem). In conclusion, the meta-analysis on the available crosssectional studies did not find any significant reduction in bone mass during prolonged l-T4 treatment resulting in reduced serum TSH in premenopausal women. The risk of the present meta-analysis missing a clinically relevant annual loss of at least 1% in premenopausal women was less than 15%. In contrast, l-T4 treatment in postmenopausal women in a dosis leading to reduced serum TSH resulted in a significant excess of annual bone loss of 0.91%/year after 9.9 years in comparison to control women.

Jens Faber, Department of Endocrinology E, Frederiksberg Hospital, DK-2000 Frederiksberg, Denmark

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Jens Faber, Arne Gam, and Kaj Siersbæk-Nielsen

Abstract.

Most serum TSH assays have a working sensitivity (i.e. the lowest TSH value with an inter-assay co-efficient of variation below 10%) around 0.15-0.4 mU/l, which also is the critical area for cut off for further thyroid profile testing when serum TSH is used as a "first line test". A new assay (BeriLux hTSH) based on chemiluminescence was evaluated, and demonstrated a theoretical sensitivity (mean + 2 sd of the zero standard) of 0.005 mU/l and a working sensitivity as low as 0.04 mU/l. Reference range was 0.18-2.60 mU/l (N=33). Sixty-eight percent (13/19) of hyperthyroid patients had serum TSH <0.005 mU/l, all had serum TSH <0.037 mU/l. We studied two groups of patients with normal free T4 and T3 indices but serum TSH <0.15 mU/l as measured by an immunoradiometric assay. Thirty-five percent (7/20) of patients with nontoxic goitre and 5% (1/20) of L-T4 treated patients had serum TSH <0.005 mU/l; and in 60% (11/20) and 30% (6/20), respectively, the levels overlapped the total range for hyperthyroidism. Serum levels of sex hormone-binding globulin expressed as percent of the reference median for the relevant sex (SHBG%) were elevated in both groups of patients (p<0.01). Approximately 50% of those with serum TSH overlapping the hyperthyroid range had serum SHBG% levels above reference range. In conclusion, this assay seems superior to most previously reported assays concerning working sensitivity, but it still leaves us with a group of clinically euthyroid patients who has unmeasurably low serum TSH. Many of these patients have increased serum SHBG%, and might in fact be subclinically hyperthyroid.

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Preben Rogowski, Jens Faber, and Kaj Siersbæk-Nielsen

Abstract.

The aim of the present work was to investigate the renal clearance of 3,3',5'-triiodothyronine (reverse T3, rT3) compared to thyroxine (T4) and 3,5,3'-triiodothyronine (T3) clearance. The urinary excretion of T4. T3 and rT3 was estimated by radioimmunoassay, serum unbound hormones (AFT4, AFT3, AFrT3) were measured using ultrafiltration technique. In 27 euthyroid controls the 24 h urinary T4 excretion was in median 1.7 nmol. T3 excretion 0.8 nmol and rT3 excretion 0.08 nmol. Serum AFT4 was in median 59 pmol/l, AFT3 7.9 pmol/l and AFrT3 2.2 pmol/l. Creatinine clearance was in median 93 ml/min. Median renal clearance of T4, T3 and rT3 were 26, 70 and 25 ml/min, and apparent tubular re-absorption was in average 77, 27 and 77%, respectively. In 18 hyperthyroid patients urinary hormone excretion was highly increased and was found parallel to the increase in serum concentrations of free hormones. Clearance and per cent tubular re-absorption of T4 and rT3 were equal to and not different from control values, but T3 clearance seemed to be increased to values higher than glomerular filtration rate (GFR). In 8 patients with hypothyroidism low urinary hormone excretion was found. Clearance of T4 and rT3 did not differ from control values, but T3 clearance was reduced.

Our data show that T4, T3 and rT3 are excreted by glomerular filtration of free hormones and suggest that tubular transport mechanisms are involved. The hypothesis is put forward that the renal handling of the thyronines is influenced by the number of the outer phenolic ring iodine atoms.

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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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Birte Nygaard, Jens Faber, Laszlo Hegedüs, and Jens Mølholm Hansen

The traditional treatment of a growing nodular non-toxic goitre has for many years been surgical resection or levothyroxine suppressive treatment. During recent years, several studies have reported promising results of 131I treatment in terms of thyroid size reduction (1–6).

This review outlines the different treatment modalities of non-toxic nodular goitre with special emphasis on 131I treatment. By the term nodular goitre we include glands with solitary or multiple thyroid nodules with uptake on a scintiscan (hot nodules).

Assessment of goitre size

Goitre is usually defined clinically, as a visible or palpable thyroid gland, and usually WHO grade 0 (absent) to grade III (large goitre) (7) is applied. This is an inaccurate definition, however, mainly due to both large inter- and intraobserver variations. Jarløv et al. (8) found an average error of 39% (range 0–170%) in the clinical assessment of thyroid size compared to ultrasonically determined volume. Therefore, the

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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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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).