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Oliver Klefter and Ulla Feldt-Rasmussen

Objective

Adult patients with GH deficiency (GHD) are characterized by a reduced muscle mass, but also reduced bone mineral density (BMD) and content (BMC), which have been ascribed to GHD per se.

The aim of this study was to investigate if changes in BMD/BMC in adult GHD patients could be due to a muscle modulating effect, and if treatment with GH would primarily increase muscle mass and strength with a secondary increase in BMD/BMC, thus supporting the present physiological concept that mass and strength of bones are mainly determined by dynamic loads from the skeletal muscles.

Method

We performed a systematic literature analysis, including 51 clinical trials published between 1996 and 2008, which had studied the development in muscle mass, muscle strength, BMD, and/or BMC in GH-treated adult GHD patients.

Results

GH therapy had an anabolic effect on skeletal muscle. The largest increase in muscle mass occurred during the first 12 months of therapy.

Most trials measuring BMD/BMC reported significant increases from baseline values. The significant increases in BMD/BMC occurred after 12–18 months of treatment, i.e. usually later than the increases in muscle parameters. Only seven trials studied both muscle and bone variables concomitantly. No trials studied the relationship between the changes in muscle and bone measurements.

Conclusion

Although in vitro studies have shown that GH has a direct effect on bone remodeling, present physiological concepts and the results of clinical trials from 1996 to 2008 suggest that the anabolic changes in muscle mass and strength may also contribute to changes in BMD/BMC in GH-treated adult GHD patients.

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Ulla Feldt-Rasmussen, Karine Bech and John Date

ABSTRACT

To study serum thyroglobulin (Tg) levels in patients with thyroid disorders compared to sex- and age-matched control subjects and to correlate the Tg levels to the thyroid function, 71 patients were investigated before treatment was started.

Serum Tg, measured by a double antibody radioimmunoassay, was elevated in all groups with thyroid disorders, as compared to their controls, but the values showed large overlaps between groups. The highest median values were seen in the two groups of patients with toxic goitres (toxic adenoma and Graves' disease). The Tg values in patients with non-toxic goitres (diffuse and nodular) and in controls showed a log normal distribution, whereas the distribution of values from patients with toxic goitres was different. No correlation was found between serum Tg and serum thyroxine, serum triiodothyronine and serum TSH, respectively.

It is concluded that determination of serum Tg is of little diagnostic value in thyroid diseases.

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Ulla Feldt-Rasmussen, Per Hyltoft Petersen and John Date

ABSTRACT

The aim of the present investigation was to describe variations in serum thyroglobulin in relation to sex and age in a group of normal persons. The method used was a modified double antibody radioimmunoassay characterized by pre-incubation at 37°C of standard or sample with antiserum, resulting in a reduced total incubation time. Both sensitivity and precision were comparable to other published methods.

Of the 152 blood-donors initially investigated, 7 were excluded due to the presence of antithyroglobulin antibodies as evidenced by a radioassay. Both sexes were equally represented with an even distribution of ages from 20-65 years.

Increased serum thyroglobulin with increasing age was demonstrated, the correlation being significant in women (Kendall's τ, P < 0.001). Detectable concentrations of serum thyroglobulin (above 1.7 μg/l) were found in 94 %. Based on the logarithmic transformation, the upper reference limits were determined for men ≦ 40 years: 36 μg/l, > 40 years: 44 μg/l (difference between groups not significant, P > 0.05), and for women ≦ 40 years: 30 μg/l, > 40 years: 60 μg/l (significant difference, P < 0.005).

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Jøgen Petersen, Ulla Feldt-Rasmussen, Flemming Larsen and Kai Siersbæk-Nielsen

Abstract. Blood mononuclear cells (MNC) from 21 patients with autoimmune thyroiditis were assayed for secretion of immunoglobulins in vitro by a reverse haemolytic plaque forming cell (PFC) assay. An anti-gen-specific assay was employed to quantify anti-thyroglobulin antibody (TgAb) secreting cells. The sensitivities of the two PFC assays were similar. The antigen specificity of the Tg-PFC assay was demonstrated by the ability of free Tg to inhibit PFC formation.

The number of spontaneous TgAb-secreting cells was low (median 3 IgG-Tg-PFC/106, range 0–35/106); TgAb activity was found in 3% (range 0–11%) of total IgG-PFC. The number of spontaneous IgG-TgAb-secreting cells correlated positively to TgAb titres in serum. MNC from most patients secreted IgG-TgAb upon polyclonal stimulation in vitro for six days with pokeweed mitogen (52 IgG-Tg-PFC/106, range 0–478/106); TgAb activity was found among 2% (range 0–8%) of total IgG-PFC. Again, pokeweed mitogen-induced TgAb secretion correlated positively to TgAb titres in serum. Finally, MNC from most patients secreted TgAb after culture with Tg. The Tg-induced response was about 1/3 of the pokeweed mitogen-induced TgAb response. Tg did not increase the production of total IgG indicating that Tg is not a polyclonal stimulus. Few TgAb-secreting MNC were discovered in euthyroid sex and age-matched control patients.

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Ulla Feldt-Rasmussen, Laszlo Hegedüs, Jens M. Hansen and Hans Perrild

Abstract. Twenty-five patients with non-toxic diffuse goitre were studied during and after 12 months of treatment with 60 μg triiodothyronine daily in order to see whether a correlation could be found between the reductions of thyroid volume, using ultrasonic scanning, and serum thyroglobulin. Thyroid function tests and thyroid volume determination were performed before treatment and after 3, 6 and 12 months of therapy in 19 patients (group 1). In patients of group 2 (n = 19) the same tests were performed at the end of 12 months treatment and 6 and 12 months after withdrawal. Before treatment all patients had a significantly increased thyroid volume compared to controls matched according to sex, age and body weight (P < 0.001). Serum thyroglobulin was elevated compared to controls (P < 0.02), with a significantly positive correlation to the thyroid volume (Spearmann's Rho = 0.52, P < 0.02). Both serum thyroglobulin and thyroid volume decreased during treatment in the majority of the patients, concomitantly in approximately half of them. After withdrawal of treatment (group 2) serum thyroglobulin showed a median increase of 54% after 6 months and remained unchanged thereafter, whereas the thyroid volume was unchanged after 6 months. These findings might support the concept that the regulation of thyroid growth and of protein synthesis and degradation might be determined by different factors.

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Nini G. Rasmussen, Peter J. Hornnes, Mimi Høier-Madsen, Ulla Feldt-Rasmussen and Laszlo Hegedüs

Abstract.

In a study of postpartum thyroiditis, thyroid function and ultrasonically determined thyroid size were evaluated in 36 thyroid autoantibody positive healthy women during pregnancy and the first postpartum year. Twelve women (33%) developed postpartum thyroiditis with permanent thyroid dysfunction in three. However, only one woman had symptoms and needed treatment. The most common type of thyroid dysfunction was a transient hyperthyroid phase as seen in 7 women. A significant increase by 20-30% in mean thyroid volume during pregnancy was demonstrated independent of development of postpartum thyroiditis. We conclude that initial thyroid volume or changes during pregnancy and post partum are not useful indicators of the development of postpartum thyroiditis. The fact that the condition is oligosymptomatic suggests that screening procedures are necessary if one wants to diagnose the earliest phases of postpartum thyroiditis.

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Nini G. Rasmussen, Peter J. Hornnes, Laszlo Hegedüs and Ulla Feldt-Rasmussen

Abstract.

Serum thyroglobulin, TSH, thyroid hormones and thyroid volume were investigated during the menstrual cycle in 10 healthy females (day 2, 9, 16, 23 and day 2 of next cycle), during pregnancy (week 18, 24, 30 and 36) and post partum (1, 2, 3, 6 and 12 months) in 20 healthy females. During the menstrual cycle median serum thyroglobulin increased from 27 (day 2) to 32 μg/l (day 23, p < 0.01 ). Serum TSH and thyroid volume demonstrated a similar increase with a positive correlation between serum thyroglobulin and thyroid volume (r = 0.65, p < 0.02). Median serum thyroglobulin was significantly increased during the whole pregnancy (week 36, 73 μg/l) compared with post partum (1 month post partum, 22 μg/l, p < 0.01), as was thyroid volume. Serum TSH was unaltered and free thyroid hormone indices decreased during pregnancy compared with post partum. No relation between changes in serum thyroglobulin and thyroid volume, TSH or thyroid hormones could be demonstrated. Serum thyroglobulin alterations thus were related to alterations in TSH and thyroid volume during the menstrual cycle. However, the increase in serum thyroglobulin and thyroid volume during pregnancy were unrelated to changes in serum TSH, indicating other mechanisms of regulation than TSH. When interpreting serum thyroglobulin levels in women, the co-existence of pregnancy and time of menstrual cycle should be taken into account in order to avoid misinterpretation of results.

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Ulla Feldt-Rasmussen, Karine Bech, John Date, Per Hyltoft Petersen and Klaus Johansen

Abstract.

Measurement of serum thyroglobulin (Tg) and its autoantibody (TgAb) by radioimmunological methods was performed in 48 patients with Graves' disease during treatment with radioiodine (n = 16) or propylthiouracil (PTU) (n = 32).

Twenty-five of the 48 patients were TgAb positive, their sera being inaccessible to measurement of serum Tg. TgAb showed only minor changes during PTU treatment, whereas TgAb fell rapidly after radioiodine, in 5 of 16 patients to unmeasurable levels, followed by a secondary rise to 4.5 times pre-treatment level after 20 weeks.

Serum Tg showed a steady increase during the first weeks after radioiodine treatment, but fell to lower levels after one year. PTU caused only minor changes in the serum Tg concentration. There was no shift in molecular sizes of either Tg or TgAb during the course of the treatments.

Five of 16 131I-treated patients developed myxoedema, 4 of whom were TgAb positive. Another 3 patients had high increases in TgAb without myxoedema.

Six of 18 patients had relapse of thyrotoxicosis after withdrawal of PTU-treatment. There was no significant difference in serum concentrations of TgAb or Tg between those developing relapse and those remaining in remission, and it is concluded that serum Tg is a poor predictor of relapse in medically treated thyrotoxicosis.

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Hans Perrild, Ulla Feldt-Rasmussen, Karine Bech, Preben Ahlgren and Jens Mølholm Hansen

Abstract. Nine consecutive patients with unilateral ophthalmopathy with suspected endocrine pathogenesis were investigated with a TRH test, a T3 suppression-test, thyroid autoantibodies and a subsequent computerized tomography (CT)-scan. All patients were clinically and biochemically euthyroid. Seven of 9 patients had a normal TRH test and 6 of 7 had a normal T3 suppression test. Slightly to moderately elevated microsomal and thyroglobulin (determined with radioimmunoassay) autoantibodies were found in 5 of 8 patients and in 1 patient thyroid stimulating immunoglobulins (TSI) were found. Three of the patients had normal thyroid function tests and no detectable thyroid autoantibodies. The subsequent CT-scan revealed that one of these had a maxillary tumour protruding into the orbita. The remaining 8 patients had enlargement of one (3 patients) or more (5 patients) eyemuscles. Two of the 8 patients had bilaterally enlarged eyemuscles, one of which was the patient with positive TSI. The remaining 6 patients had unilateral extraocular muscle enlargement. Thus, 2 of 9 patients had ophthalmopathy without thyroid dysfunction so-called isolated autoimmune ophthalmopathy or Graves' ophthalmopathy.

Thyroid function tests seem to be of limited value in the diagnosis between endocrine and non-endocrine eye disease, and we recommend the use of diagnostic imaging (e.g. CT-scan) in patients with unilateral exophthalmus in order to diagnose malignant processes.

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Ulla Feldt Rasmussen, Axel Kemp, Karine Bech, Stig Nistrup Madsen and John Date

Abstract.

Serum concentrations of thyroglobulin, its antibody, and thyroid stimulating antibodies were studied in 32 patients referred to a department of eye-diseases for exophthalmos. Twenty-three of the patients were or had been medically treated for Graves' disease, one had toxic nodular goitre, one subclinical myxoedema, three euthyroid exophthalmos and four were shown to have non-endocrine eye-disease.

In patients with medically treated Graves' disease serum thyroglobulin was significantly elevated (P < 0.02), the still toxic patients accounting for the highest values. Both thyroid stimulating and thyroglobulin antibodies were detectable in 4 of 18 patients. The rest of the patients had normal concentrations of thyroglobulin and undetectable thyroid stimulating antibodies, but 3 patients had measurable thyroglobulin antibodies. In Graves' patients there was no correlation between serum concentrations of thyroid stimulating antibodies and thyroglobulin, and no clear difference between the frequency of thyroid stimulating or thyroglobulin antibodies in the patients with persistent elevation of circulating thyroid hormones and those remaining euthyroid.

A relation between the thyroid autoantibodies, thyroglobulin and the thyroid hormonal level or severity of the exophthalmic state could not be demonstrated.

It is suggested that hyperthyroidism and exophthalmos are separate disorders, and immunological phenomena probably involved in the pathogenesis of exophthalmos associated with Graves' disease appear to be reflected only locally.