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Louise A Lynggård, Eigil Husted Nielsen, and Peter Laurberg

Background

Neuroendocrine tumours are most frequently located in the gastrointestinal organ system or in the lungs, but they may occasionally be found in other organs.

Case

We describe a 56-year-old woman suffering from a carcinoid syndrome caused by a large serotonin-secreting pituitary tumour. She had suffered for years from episodes of palpitations, dyspnoea and flushing. Cardiac disease had been suspected, which delayed the diagnosis, until blood tests revealed elevated serotonin and chromogranin A in plasma. The somatostatin receptor (SSR) scintigraphy showed a single-positive focus in the region of the pituitary gland and MRI showed a corresponding intra- and suprasellar heterogeneous mass. After pre-treatment with octreotide leading to symptomatic improvement, the patient underwent trans-cranial surgery with removal of the tumour. This led to a clinical improvement and to a normalisation of SSR scintigraphy, as well as serotonin and chromogranin A levels.

Conclusion

To our knowledge, this is the first reported case of a serotonin-secreting tumour with a primary location in the pituitary.

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DANIEL GLINOER, DIETER HESCH, RAPHAËL LAGASSE, and PETER LAURBERG

In 1986, a survey on the management of hyperthyroidism due to Graves' disease was undertaken in Europe. The survey was based on the results of a questionnaire mailed to all clinicians who were members of the ETA.

Why was it decided to organize an international survey on Graves' hyperthyroidism? There were four main reasons for 'revisiting' this well-known disease. First, clinical thyroidology is changing rapidly owing to the introduction of new techniques for the diagnosis and follow-up of patients with Graves' disease (such as assays for the quantification of free hormones, TSH-receptor antibody measurements, 123I scintigraphy). It was therefore decided to assess the impact of these innovations. Second, Graves' disease is a common endocrine disorder, for which three therapeutic options are available: antithyroid drug therapy, radioiodide administration, and surgery. Each of these treatments has advantages and drawbacks and recently, new recommendations for therapy have been proposed by Hennemann et

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Inge Bülow Pedersen, Peter Laurberg, Nils Knudsen, Torben Jørgensen, Hans Perrild, Lars Ovesen, and Lone Banke Rasmussen

Background: Thyroid autoimmunity is more common in females than in males. One possible explanation for this female preponderance may be the effect of oestrogens on the immune system. It has also been suggested that foetal microchimerism involving transfer of foetal cells into maternal tissue during pregnancy may play an important role.

Objective: We investigated the association between the presence of circulating thyroid autoantibodies and previous pregnancy, parity and the use of oral contraceptives (OCs) and hormone replacement therapy (HRT) in a population cohort.

Methods: We examined 3712 women randomly selected from the general population. Serum was analysed for thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) using assays based on an RIA technique (DYNO test). Data were analysed in logistic regression models to adjust for possible confounders. Women previously treated for thyroid disease or with pregnancy within 1 year prior to the study were excluded from the analyses.

Results: In both univariate and multivariate models and whether the presence of TPO-Ab and Tg-Ab was investigated alone or in combination, findings were negative with respect to an association between circulating thyroid antibodies and previous pregnancy, number of pregnancies, parity and previous abortion. There was no association between thyroid autoantibodies and use of OCs. Women aged 60–65 years receiving HRT now or previously had a lower prevalence of Tg-Ab (univariate, P = 0.01; multivariate, P = 0.02). No such association was observed between HRT and TPO-Ab.

Conclusion: In this population study there was no association between previous pregnancy, parity and thyroid antibodies, which argues against the role of microchimerism as a trigger of thyroid autoimmunity. Exogenous oestrogens may reduce aspects of autoimmunity.

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Peter Laurberg, Poul Erik Buchholtz Hansen, Eigil Iversen, Sigurd Eskjær Jensen, and Jørgen Weeke

Abstract. One hundred and twenty-four patients with newly diagnosed hyperthyroidism received a combined thionamid-thyroxine medical therapy for approximately 2 years. According to the estimated goitre size before therapy and the type of goitre the patients were divided into 4 groups: Graves' disease no goitre (n = 19). Graves' disease small goitre (n = 57), Graves' disease medium or large goitre (n = 23), multinodular goitre (n = 25). The median follow-up period after cessation of medication was 64 (range 11–141) months.

The remission rates in the different groups during follow-up were calculated using life table analysis. Graves' patients with no goitre or a small goitre had a significantly better outcome (remission % after 5 years 82.5 ± 15.4 (se) and 71.5 ± 7.8, respectively) than Graves' patients with a medium size or large goitre (remission % after 5 years 37.0 ± 11.1) (P <0.025). Most patients with multinodular goitre had a relapse within the first year after stop of medication (remission % after 5 years 15.5 ± 10.1). Hence patients with Graves' disease having a small thyroid gland should be treated medically while surgery or radioiodine may be a more reasonable choice in Graves' patients with medium size or large goitres. Medically treated patients with toxic multinodular goitres have a very small chance of prolonged remission if medication is stopped.

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Stine L Andersen, Susanne B Nøhr, Chun S Wu, Jørn Olsen, Klaus M Pedersen, and Peter Laurberg

Background

Placental transport of iodide is required for fetal thyroid hormone production. The sodium iodide symporter (NIS) mediates active iodide transport into the thyroid and the lactating mammary gland and is also present in placenta. NIS is competitively inhibited by thiocyanate from maternal smoking, but compensatory autoregulation of iodide transport differs between organs. The extent of autoregulation of placental iodide transport remains to be clarified.

Objective

To compare the impact of maternal smoking on thyroglobulin (Tg) levels in maternal serum at delivery and in cord serum as markers of maternal and fetal iodine deficiency.

Methods

One hundred and forty healthy, pregnant women admitted for delivery and their newborns were studied before the iodine fortification of salt in Denmark. Cotinine in urine and serum classified mothers as smokers (n=50) or nonsmokers (n=90). The pregnant women reported on intake of iodine-containing supplements during pregnancy and Tg in maternal serum at delivery and in cord serum were analyzed.

Results

In a context of mild-to-moderate iodine deficiency, smoking mothers had significantly higher serum Tg than nonsmoking mothers (mean Tg smokers 40.2 vs nonsmokers 24.4 μg/l, P=0.004) and so had their respective newborns (cord Tg 80.2 vs 52.4 μg/l, P=0.006), but the ratio between Tg in cord serum and maternal serum was not significantly different in smokers compared with nonsmokers (smoking 2.06 vs nonsmoking 2.22, P=0.69).

Conclusion

Maternal smoking increased the degree of iodine deficiency in parallel in the mother and the fetus, as reflected by increased Tg levels. However, placental iodide transport seemed unaffected despite high thiocyanate levels, suggesting that thiocyanate-insensitive iodide transporters alternative to NIS are active or that NIS in the placenta is autoregulated to keep iodide transport unaltered.

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Bjarne Bach Pedersen, Peter Laurberg, Merete Sanvig Christensen, and Stig Pors Nielsen

Abstract.

A model for direct measurement of hormone release from the canine parathyroid gland is described. The two separate thyroid-parathyroid gland complexes were isolated in situ and perfused independently using a synthetic medium with a welldefined concentration of ionized calcium (Ca++). The concentration of parathyroid hormone (PTH) in the effluent was measured by radioimmunoassay, using an antiserum to bovine PTH that cross-reacts with canine PTH. Displacement curves of dilutions of effluent samples were similar to those of bovine PTH (1–84). During infusion of 1.49 mmol/l Ca++ the PTH release was constant for more than 4 h. Variations in Ca++ from 1.56 to 1.15 or 2.15 mmol/l induced rapid and sustained stimulation or suppression of PTH release. The retained ability of the preparation was ascertained by recording the response to infusion of calcium free medium at the end of each experiment.

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Peter Laurberg, Göran Wallin, Leif Tallstedt, Mirna Abraham-Nordling, Göran Lundell, and Ove Tørring

Introduction

Autoimmunity against the TSH receptor is a key pathogenic element in Graves' disease. The autoimmune aberration may be modified by therapy of the hyperthyroidism.

Objective

To compare the effects of the common types of therapy for Graves' hyperthyroidism on TSH-receptor autoimmunity.

Methods

Patients with newly diagnosed Graves' hyperthyroidism aged 20–55 years were randomized to medical therapy, thyroid surgery, or radioiodine therapy (radioiodine was only given to patients ≥35 years of age). l-thyroxine (l-T4) was added to therapy as appropriate to keep patients euthyroid. Anti-thyroid drugs were withdrawn after 18 months of therapy. TSH-receptor antibodies (TRAb) in serum were measured before and for 5 years after the initiation of therapy.

Results

Medical therapy (n=48) and surgery (n=47) were followed by a gradual decrease in TRAb in serum, with the disappearance of TRAb in 70–80% of the patients after 18 months. Radioiodine therapy (n=36) led to a 1-year long worsening of autoimmunity against the TSH receptor, and the number of patients entering remission of TSH-receptor autoimmunity with the disappearance of TRAb from serum during the following years was considerably lower than with the other types of therapy.

Conclusion

The majority of patients with Graves' disease gradually enter remission of TSH-receptor autoimmunity during medical or after surgical therapy, with no difference between the types of therapy. Remission of TSH-receptor autoimmunity after radioiodine therapy is less common.

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Jørgen Weeke, Stig Engkjær Christensen, Aage Prange Hansen, Peter Laurberg, and Knud Lundbæk

Abstract.

The influence of somatostatin on serum TSH, 3,5,3′-triiodothyronine (T3), free T3, thyroxine (T4), free T4 and 3,3′,5′-triiodothyronine (reverse T3, rT3) was studied in 5 healthy young subjects, in 7 young patients with juvenile type diabetes on a fixed daily insulin dose, and in 5 patients with treated myxoedema. Blood samples were taken hourly during a 24 h control period and during a 24 h somatostatin infusion period.

Somatostatin infusion obliterated the night increase in serum TSH in all three groups. However, the lower daytime serum TSH was not altered by somatostatin. It has earlier been shown that somatostatin inhibits the TSH secretion induced by TRH. Taken together these findings suggest that the high TSH level at night is induced by a hypothalamic TRH surge, while the lower day level of TSH is quite independent of hypothalamic TRH.

Somatostatin infusion was accompanied by a minor fall in serum T4 in all groups. In normal subjects and diabetics serum free T3 fell 23 ± 6% and 25 ± 6%, respectively, during 24 h somatostatin infusion. In patients with treated myxoedema, serum free T3 was not significantly affected. These results are consistent with a decrease in thyroidal secretion during somatostatin infusion, as the cause for the fall in serum T3 in normal subjects and in patients with diabetes, while the monodeiodination of T4 to T3 in peripheral tissues is unaffected. However, an extrathyroidal effect of somatostatin on iodothyronine metabolism might also exist since serum rT3 increased 49 ± 19% in patients with treated myxoedema. In normal subjects and diabetic patients only a trend towards such a variation was observed.

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Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, and Peter Laurberg

Objective

Few population-based studies have described the epidemiology of subtypes of hyperthyroidism.

Design

A prospective population-based study, monitoring two well-defined Danish cohorts in Aalborg with moderate iodine deficiency (n=311 102) and Copenhagen with only mild iodine deficiency (n=227 632).

Methods

A laboratory monitoring system identified subjects with thyroid function tests suggesting overt hyperthyroidism (low s-TSH combined with high s-thyroxine or s-triiodothyronine). For all subjects, we collected information on medical history, thyroid scintigraphy and thyroid hormone receptor antibody (TRAb) measurement. Information was used to disprove or verify primary overt hyperthyroidism and to subclassify hyperthyroidism into nosological disorders.

Results

From 1997 to 2000 (2 027 208 person-years of observation), we verified 1682 new cases of overt hyperthyroidism. The overall standardized incidence rate (SIR) per 100 000 person-years was 81.6, and was higher in Aalborg compared with Copenhagen (96.7 vs 60.0, P<0.001), giving an SIR ratio (SIRR (95% confidence interval (CI))) between moderate versus mild iodine-deficient areas of 1.6 (1.4–1.8). Nosological types of hyperthyroidism (percentage/SIRR (95% CI)): multinodular toxic goitre (MNTG) 44.1%/1.9 (1.6–2.2), Graves' disease (GD) 37.6%/1.2 (0.99–1.4), solitary toxic adenoma (STA) 5.7%/2.4 (1.3–3.5), ‘mixed type’ hyperthyroidism (TRAb-positive, scintigraphicly multinodular) 5.4%/6.0 (3.0–12), subacute thyroiditis 2.3%/0.9 (0.4–1.4), postpartum thyroid dysfunction 2.2%/1.6 (0.8–3.0), amiodarone-associated hyperthyroidism 0.8%/7.1 (1.1–65), hyperthyroidism after thyroid radiation 0.7%/12.3 (0.8–50), lithium-associated hyperthyroidism 0.7%/0.97 (0.4–4.8) and hyperthyroidism caused by various other factors 0.7%. Lifetime risk for overt hyperthyroidism was 10.5%/6.5%/2.4% (females/all/males).

Conclusion

Hyperthyroidism was common in Denmark with MNTG and GD as dominating entities. The higher incidence of hyperthyroidism in the most iodine-deficient region was caused by higher frequency of MNTG, ‘mixed-type’, STA and amiodarone-associated hyperthyroidism.

Free access

Allan Carlé, Nils Knudsen, Inge Bülow Pedersen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, and Peter Laurberg

Objective

To characterize thyroid hormone levels at the time of diagnosis in the nosological types of thyrotoxicosis diagnosed in the population and to analyze determinants for serum thyroxine (T4) and tri-iodothyronine (T3).

Design

Population-based study of thyrotoxicosis at disease onset.

Methods

In the period 1997–2000, we prospectively identified all patients diagnosed with incident primary overt thyrotoxicosis in a Danish population cohort and classified patients into ten well-defined nosological types of disease (n=1082). Untreated levels of serum T3, T4, and T3:T4 ratio were compared and related to sex, age, level of iodine deficiency, smoking status, alcohol intake, iodine supplement use, co-morbidity, and TSH receptor antibodies (TRAbs) in multivariate models.

Results

Graves' disease (GD) patients had much higher levels of T3 and higher T3:T4 ratio at diagnosis compared with other thyrotoxic patients, but with a profound negative association between hormone levels and age. In GD, patients diagnosed in the area with more severe iodine deficiency had lower levels of T3 and T4. TRAb-negative GD patients had biochemically mild thyrotoxicosis. Higher age was also associated with lower degree of biochemical thyrotoxicosis in nodular toxic goiter. We found no association between serum T3 and T4 and sex, smoking habits, iodine supplements, alcohol intake, or co-morbidity in any type of thyrotoxicosis.

Conclusions

The study gives new insight into the hormonal presentation of thyrotoxicosis and showed that young age, positive TRAb levels, but also residency in the area with higher iodine intake was positively associated with biochemical disruption in GD.