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AK Rasmussen, B Nygaard and U Feldt-Rasmussen

OBJECTIVE: Radioiodine ((131)I) used to obtain euthyroidism in thyrotoxic patients is suspected of having a worsening or provoking effect on thyroid-associated ophthalmopathy (TAO), an autoimmune disease closely related to Graves' disease. DESIGN: This review summarises the existing literature and describes risk factors influencing the course of TAO including thyroid function, cigarette smoking and treatment of Graves' hyperthyroidism (especially (131)I therapy). CONCLUSION: It is recommended that patients who may be at a greater risk of worsening ophthalmopathy are considered when choosing the modality of therapy of hyperthyroidism and also in deciding whether prophylactic systemic glucocorticoid treatment is indicated.

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T Zimmermann-Belsing, B Nygaard, AK Rasmussen and U Feldt-Rasmussen

OBJECTIVE: Antithyroid drug treatment (ATD) is used world-wide in the treatment of thyrotoxicosis in patients with Graves' disease (GD). The main problem is a relapse rate of 30 to 50% within 2 years after the treatment has stopped. The measurement of thyrotropin receptor antibodies (TRAb) in serum has been used to confirm the diagnosis of GD in selected patients with a diagnostic specificity of 70 to 90%. However, in predicting the recurrence of thyrotoxicosis after discontinuing ATD it has been of little value. The aim of this study was to evaluate the ability of TRAb measured by the more sensitive recombinant human TSH receptor method to predict risk of recurrence of GD after discontinuing ATD. MATERIALS, PATIENTS AND METHODS: One hundred and twenty nine patients with newly diagnosed GD were included. Of these, 58 had relapse of hyperthyroidism in a follow-up of at least 11 months (median 18 months, range 11-49) after discontinuing ATD. In 122 Graves' patients TRAb were measured at the time of diagnosis and in all patients when discontinuing ATD by a competitive radioreceptor assay using recombinant human TSH receptors (TRAK human assay). RESULTS: We found an increased diagnostic specificity (99%) compared with the old TRAK porcine assay. The predictive values of a positive and negative test in relation to the prediction of a relapse of GD were found to be only 55% and 62% respectively when using a cut-off level of 1.5 IU/l, and the predictive value of a positive test decreased to 49% and of a negative test to 60% at a lower cut-off limit (1 IU/l). CONCLUSION: Our study confirms that the new TRAK human assay had a superior diagnostic sensitivity in comparison with the old TRAK porcine assay. Despite the higher diagnostic sensitivity of the TRAK human method, we could not find any improvement of predictive values for relapse of hyperthyroidism in the measurement of TRAb at the end of ATD.

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J. Date, M. Blichert-Toft, U. Feldt-Rasmussen and V. Haas

Abstract. The effect of subtotal thyroid resection for thyrotoxicosis on concentrations of serum thyroid hormones and thyroglobulin (Tg), was determined in 10 patients during operation and the subsequent 18 days. Mean serum Tg responded drastically, increasing from a pre-operative value of 0.30 nmol/l to a peak value of approximately 26 nmol/l during operation followed by a gradual decline to levels lower than before surgery on day 18. Mean serum total thyroxine was 114 nmol/l pre-operatively and free thyroxine index (FT4I) 105 units. Both fluctuated only slightly during operation. Postsurgically, the mean values decreased to below 50% of the pre-operative level. Mean serum total triiodothyronine (TT3) was 1.46 nmol/l pre-operatively. It decreased during operation, reaching a nadir of 0.55 nmol/l on day 2, whereafter the concentration increased slightly. Mean serum reverse T3 (rT3) was 0.45 nmol/l pre-operatively, increased 62% during surgery, and decreased postsurgically. The mean value of serum thyroid stimulating hormone (TSH) was 0.61 mU/l pre-operatively and remained below 1 mU/l during and after operation, but from day 10 concentration began to rise steadily. It is concluded that the vast release of Tg during thyroid resection did not contribute to the concentration of serum T4 to an extent of clinical relevance.

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U. Feldt-Rasmussen, P. Hyltoft Petersen, O. Blaabjerg and M. Hørder

Abstract.

From 5 young males and 5 young females blood was drawn under highly standardized conditions at 6 to 10 occasions during 4 months. The serum constituents thyroglobulin, thyroxine, triiodothyronine, T3-uptake test, TBG and TSH were determined, and four indices were calculated.

The biological intra-individual coefficients of variation were below 0.14 for thyroglobulin, and the inter-individual coefficients of variation ranged from zero for T3-uptake test to 0.35 for thyroglobulin.

All results were within the generally accepted reference ranges for normals. Within these ranges the calculations of indices for free thyroxine and triidothyronine according to T3-uptake test and TBG, did not significantly reduce the coefficients of variation for these serum constituents.

Thyroglobulin concentrations did not correlate to any of the measured or calculated constituents. The knowledge of these intra- and inter-individual variations of serum thyroglobulin in healthy persons is of importance for the interpretation of variations found in patients.

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T Zimmermann-Belsing, G Brabant, JJ Holst and U Feldt-Rasmussen

The identification and sequencing of the ob gene and its product, leptin, in 1994 opened new insights in the study of the mechanisms controlling body weight and led to a surge of research activity. Since its discovery, leptin has been the subject of an enormous amount of work especially within the fields of nutrition, metabolism and endocrinology. Leptin is accepted as an adipose signal, and even though the underlying mechanisms are not fully clarified, leptin, in addition to the thyroid hormones, is believed to be involved in regulation during the switch from the fed to the starved state. It is not clear whether leptin and the melanocortin pathways interact with the thyroid axis under physiological conditions other than during starvation or in response to severe illness, both states in which the hypothalamo-pituitary-thyroid axis may be severely suppressed. In addition to the suggested central relationship between leptin and thyroid hormones, there might also be a peripheral relationship although this effect is not clear. Both thyroid hormones and leptin might be involved in the adaptive thermogenesis through mitochondrial uncoupling proteins and heat production because both thyroxine and triiodothyronine are involved in the starvation-induced decrease in thermogenesis. Both rodent and human studies of leptin have failed to show any consistent relationship between thyroid function and serum leptin concentrations. However, leptin might have an important role in thyroid pathophysiology due to thyroid hormone involvement in thermogenesis and regulation of uncoupling proteins. In this review, we have focused on leptin in relation to thyroid pathophysiology.

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Å. Krogh Rasmussen, L. Kayser, K. Bech, U. Feldt-Rasmussen, H. Perrild and K. Bendtzen

Abstract.

Interleukin 6 has been suggested as second mediator of the effects of interleukin 1 in some cell systems. Interleukin 1 has previously been shown to inhibit the function of human thyrocytes in secondary cultures. We have therefore studied the influence of interleukin 6 (10−1−5·107 U/l) on the function of thyroid cells. Recombinant interleukin 6 slightly inhibited the production of cAMP, but failed to influence the production of thyroglobulin or the DNA content. Endotoxins (lipopolysaccharides from Salmonella abortus equi or Yersinia enterocolitica) had only a slightly inhibitory effect on thyroid cell functions, and the effect of interleukin 6 could not by itself be explained by endotoxin contamination. The effect of interleukin 6 did not mimick effects on thyroid cells afforded by recombinant interleukin 1α and 1β. Furthermore, antibodies to interleukin 6 were not able to inhibit the interleukin 1β-induced inhibition of thyroid cell functions. In conclusion, it is unlikely that interleukin 6 by itself mediates the biological effects of interleukin 1 on human thyroid cells.

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Å. Krogh Rasmussen, L. Kayser, K. Bech, U. Feldt-Rasmussen, H. Perrild and K. Bendtzen

Abstract

The effects of human recombinant interleukin 1α (20 pg/1-2 μg/l) and 1β (200 pg/1-20 μg/l) on two systems of thyroid cells have been compared. The thyroglobulin and cAMP secretion and the DNA content of human thyroid cells cultured in monolayer and of continuously grown rat thyroid cells, Fischer rat thyroid cell line have been studied. The growth of the rat thyroid cell line was inhibited by interleukin 1β (20 ng/1-20 μg/l), but not by interleukin 1α. None of the cytokines changed the cAMP production of the rat thyroid cells. In contrast, both cAMP production and thyroglobulin secretion were inhibited dose-dependently by the cytokines in human thyroid cells in secondary cultures. These results caution the interpretation and extrapolation of changes induced by interleukin 1 from one cell system to the other.

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ML Hartoft-Nielsen, AK Rasmussen, A Kaas, U Feldt-Rasmussen and K Buschard

OBJECTIVE: Changes in the functional state of beta cells by neonatal stimulation or adolescent suppression have reduced the incidence of type 1 diabetes mellitus in animal models. The aim of this study was to evaluate the effect of manipulation of the activity of the thyroid gland by neonatal stimulation or by adolescent suppression on the prevalence of spontaneous autoimmune thyroiditis (AIT) in rats. METHODS: Bio-Breeding/Worcester (BB) rats were treated neonatally with sodium iodine (NaI) or thyroid stimulating hormone (TSH), or during adolescence by triiodothyronine (T(3)), and the lymphocytic infiltration in the thyroid gland was evaluated. RESULTS: Neonatal treatment with NaI decreased the prevalence of AIT to 32+/-9% compared with 66+/-5% in the controls (P<0.002), mainly caused by a reduction among the female rats (13+/-9% vs 52+/-8%, P<0.006). TSH had no effect. Post neonatal suppression of the thyroid gland by T(3) had a biphasic response. Early in adolescence the overall prevalence was 14+/-7% compared with 66+/-5% in the controls (P<10(-5)); for female rats AIT was prevented (0+/-0%) compared with 52+/-8% in the controls (P<0.0003) and in male rats the values were 29+/-13% compared with 80+/-6% in the controls (P<0.001). Treatment with T(3) later in adolescence increased the overall prevalence to 81+/-7% compared with 66+/-5% in the controls (not significant). For female rats the prevalence increased to 78+/-9% compared with 52+/-8% in the controls (P=0.04). The degree of thyroiditis among the affected animals was similar in all groups. CONCLUSION: Neonatal stimulation of the thyroid gland by iodine or early adolescent suppression by T(3) reduced the prevalence of AIT whereas T(3) given later increased the prevalence of thyroiditis in rats. Thyroid activity at various ages seems to be of importance for the development of autoimmune thyroiditis.

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TV Elberling, AK Rasmussen, U Feldt-Rasmussen, M Hording, H Perrild and G Waldemar

OBJECTIVE: In the acute, thyrotoxic phase, patients with Graves' disease often have both thyrotoxic and neuropsychiatric symptoms. The purpose of this prospective study was to examine health-related quality of life (HRQOL) in newly diagnosed and untreated Graves' patients and the effect of antithyroid medical treatment on HRQOL. In addition, we examined the potential influence of thyroid hormones and psychiatric symptoms on the impairment of HRQOL in the thyrotoxic phase. METHODS: A total of 30 consecutively referred patients with newly diagnosed and untreated Graves' disease and 34 age-, sex- and education-matched healthy volunteers were included in the study. HRQOL was assessed with the Medical Outcome Study 36-item Short-Form Health Status Survey (SF-36) before treatment, after reaching euthyroidism and 1 year after initiation of treatment. RESULTS: In the thyrotoxic phase of Graves' disease, HRQOL was significantly impaired, in physical, mental and social dimensions. After reaching euthyroidism, the patients reported much fewer limitations on the subscales of SF-36. One year after initiation of treatment, all SF-36 scores had normalized. However, in some patients, HRQOL continues to be impaired even 1 year after initiation of treatment, as reviewed by the individual analysis. The reduced HRQOL in the acute phase of Graves' disease was correlated to depressive and anxiety symptoms, but thyroid-associated orbitopathy also influenced HLQOL. CONCLUSIONS: Impaired HRQOL is common in the acute phase of Graves' disease. A significant proportion of the patients demonstrated persistent HRQOL impairment 1 year after initiation of treatment. Improvement of HRQOL in these patients remains a challenge for the clinician.

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U Feldt-Rasmussen, AK Rasmussen, H Mersebach, KM Rosenberg, L Hasholt and SA Sorensen