Thyrotoxic effect of high iodine doses on xenotransplanted autoimmune thyroid tissue in athymic nude mice.
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Biomedical subjects
Publications and source records attributed to C R Pickardt.
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Goitre growth was investigated in rats receiving a low iodine diet (less than 0.1 microgram iodine/g) and either 1 g/l KClO4 or 1 g/l propylthiouracil (PTU), or a combination of KClO4 or PTU with 50.82 nmol/1 T3 in tap water for 3 weeks. To investigate goitre involution, rats with iodine-deficient goitres were treated for 3 weeks either with T3 (0.5 microgram T3/day = 0.768 nmol/day), iodide (0.5 or 2.7 micrograms KI/day) or a combination of T3 with both iodide doses. Histology together with total DNA distinguished between hypertrophy and hyperplasia of the gland. During goitre growth there was highly significant correlation between goitre weight and TSH serum level (r = 0.93, P less than 0.001). Thyroid total DNA, however, was only weakly correlated to TSH but was inversely related to the degree of iodine deficiency. During goitre regression, TSH levels were normalized, histological signs of hypertrophy had disappeared, and thyroid weight was nearly normalized in all therapy groups. Total DNA, however, was normalized only with 2.7 micrograms KI/day (95 +/- 18 micrograms DNA/gland), and still elevated in all other groups. The highest DNA levels were found under T3 therapy (143 +/- 21 micrograms DNA/gland) and under 0.5 microgram KI/day (161 +/- 19 micrograms DNA/gland). Reduction of total DNA was independent of TSH, but followed replenishment of the iodine content of the glands. We conclude that TSH mainly induces hypertrophy, whereas thyroid hyperplasia is mainly regulated by the intracellular iodine content.
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For further characterization immunoglobulins G (IgG) of 14 patients with Graves' disease were fractionated on Protein A bound Sepharose. Sufficiently enriched IgG-subclasses were obtained despite incomplete separation. TSH displacing activity (TDA) was not homogeneously distributed in the subclasses, however IgG1 was most predominant in TDA followed by IgG3, IgG2 being essentially inactive. In two subjects TDA in whole IgG gave positive results in subclasses after fractionation, thus providing evidence, that it would be theoretically possible to move sensitivity of the method close to 100% after subfractionation. TDA was not enriched together with thyroid cell antibodies. We conclude from these results that TDA-IgG is characterized by restricted heterogeneity notwithstanding the incomplete separation of the IgG-subclasses.
In the Southern Highlands of Tanzania the prevalence of endemic goitre due to iodine deficiency is in the range of 90% and hypothyroidism in the range of 50% of schoolchildren. The present study confirms these data and documents the beneficial effect of Lipiodol injections on thyroid function in children around the age of puberty compared with untreated children from the same villages. On the other hand, a decrease in the prevalence of goitre could not be shown. A beneficial effect is shown for infants of mothers who received iodine during pregnancy. It seems that this form of supplementation is sufficient for breast fed children for more than three years, even when a second child has been delivered in the meantime. In contrast, older siblings of these babies may become hypothyroid when breast feeding is stopped. The determination of thyroid autoantibodies in iodine treated and untreated children and in young adults showed no increasing prevalence of positive findings thus excluding iodine induced chronic thyroiditis at least in the young target population.
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Thickening of eye muscles in endocrine orbitopathy can be demonstrated particularly impressively in coronary computed tomograms. However, when measuring the height and width of rectus eye muscles manifesting pathologic changes, the measurement is increased by a deviation from the coronary section plane; this is due to different tilting of the gantry. This often leads to an incorrect stage classification and makes objective observation of the course (e.g., under therapy) impossible. By converting the measured values into the actual extent of the muscles by means of the cosine set, appreciable changes in the pattern and frequency of affection of the rectus eye muscles were found in 121 patients examined.
To evaluate the effect of Cyclosporin A in the management of Graves' ophthalmopathy, we treated 13 patients with severe euthyroid endocrine eye disease with the immunosuppressive drug. Follow up consisted of clinical investigation, laboratory evaluation with detailed thyroid function tests and complete ophthalmological assessments including A and B scan ultrasound and computerized tomography (CT) of the orbits. Cyclosporin A given over 4-7 months resulted in improvement of clinical signs and symptoms of the disease due to a positive effect of the drug on soft tissue changes. The more objective methods did not demonstrate any unequivocal change in proptosis, visual acuity, intraocular pressure and thickness of extraocular muscles. Cyclosporin A was not able to stop acute progression of ophthalmopathy in one patient and did not obviate surgical decompression of the orbits in two more patients. There was no measurable effect of treatment on the underlying immunological process with regard to thyroid disease.
To investigate the exaggerated prolactin (PRL) responsiveness to thyrotropin-releasing hormone (TRH) in patients with benign breast disease (BBD), 18 patients and 13 healthy controls underwent an 8-week-long thyroid hormone treatment. The clinical effect of thyroid hormones on cyclical mastodynia and concomitant galactorrhea was evaluated. TRH-stimulated PRL and thyroid-stimulating hormone (TSH) responses and thyroxine, triiodothyronine, thyroxine-binding globulin, as well as serum estradiol and progesterone levels, were measured before and during hormone treatment. Thirteen of the patients and one of the controls had euthyroid diffuse goiter. Patients and controls had normal thyroid function parameters. During thyroid hormone treatment, significantly elevated TRH-induced PRL responses of the patients decreased by 50% and reached levels of the controls, whereas responses of the controls decreased insignificantly. Patients exhibited significantly lower serum progesterone levels than the controls; the estradiol levels were not different. Thyroid hormone treatment had no significant influence on luteal function of patients or controls. In 16 of 18 patients thyroid hormones were of benefit to mastodynia, whereas galactorrhea remained unaffected.
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Thyrotropin releasing hormone is thought to be a tonic stimulator of the pituitary TSH secretion regulating the setpoint of the thyrotrophs to the suppressive effect of thyroid hormones. The peptide stimulates the release of normal and elevated prolactin. ACTH and GH may increase in response to exogenous TRH in pituitary ACTH and GH hypersecretion syndromes and in some extrapituitary diseases. The pathophysiological implications of extrahypothalamic TRH in humans are essentially unknown. The TSH response to TRH is nowadays widely used as a diagnostic amplifier in thyroid diseases being suppressed in borderline and overt hyperthyroid states and increased in primary thyroid failure. In hypothyroid states of hypothalamic origin, TSH increases in response to exogenous TRH often with a delayed and/or exaggerated time course. But in patients with pituitary tumors and suprasellar extension TSH may also respond to TRH despite secondary hypothyroidism. This TSH increase may indicate a suprasellar cause for the secondary hypothyroidism, probably due to portal vessel occlusion. The TSH released in these cases is shown to be biologically inactive.
The risk of recurrent hyperthyroidism can be eliminated indefinitely in patients with autonomously functioning thyroid tissue (AFTT) by selective surgery or radioiodine, whereas medical treatment inhibits only the actual thyroid hormone over-production. Therefore, AFTT should be removed. In immunogenic hyperthyroidism the natural history of the disease can be influenced only symptomatically. The relapse rate after medical treatment is more than 50%. After surgical or radioactive therapy long-term remission of hyperthyroidism, not of the underlying thyroid disease can be achieved more effectively. Therefore surgical treatment should be preferred.
One of the main problems in establishing isolated thyroid follicles in vitro is their tendency to form inside-out follicles. The reason for this change in polarity is unknown. We describe here a method for the preparation of stable thyroid follicles with preserved polarity for at least 6 days. Isolated follicles were obtained by infusion of collagenase (1.5 mg/ml) dissolved in minimal essential medium into the artery of intact thyroid glands. The morphological and functional properties of these follicles were compared to inside-out follicles. These inside-out follicles were obtained by digestion of minced thyroid tissue in a collagenase (1 mg/ml) solution. The polarity of follicles was proved by morphological criteria. Follicles with preserved polarity did not change polarity for at least 6 days in the presence of 1% or 5% fetal calf serum. As the culture conditions for both preparation methods were identical, we conclude that the preparation method rather than the culture condition is responsible for the preservation of cell polarity of isolated thyroid follicles in our system. Increases in cyclic AMP levels induced either by bovine thyrotropin (10(-3) U/ml) or by isoproterenol (10(-6) M) as well as iodide uptake and organification were rapid and significant in right-side-right follicles but not in inside-out follicles. Therefore the TSH receptor and the beta-adrenergic receptor appear to be exclusively located at the basal membrane of follicular cells. In addition, iodide uptake apparently is unidirectional.
UNLABELLED: The Ukinga and Uwanji regions, located in the southern highlands of Tanzania, were studied for the degree of iodine deficiency and the incidence of goitre and hypothyroidism, respectively. A urinary iodine excretion as low as 17.6 +/- 9.3 micrograms/g creatinine was observed in Wangama village. The mean goitre prevalence in 27 villages in Uwanji ranged between 65 and 96% (n = 3031 schoolchildren). Of 681 pregnant women from Ukinga 79.6% had goitre. The prevalence of cretinism as estimated on clinical criteria was 3% in Magoye (Uwanji). A normal serum TSH (below 2.1 mU/l) was observed in only 12 out of 66 school children before iodine prophylaxis, whereas the T4/TBG ratio was decreased in 36 of 63 cases. Blood spot TSH levels in newborn infants (n = 219) from mothers without iodine supplementation were above 12 mU/l in 45%. In contrast, only 20.3% of the newborn (n = 118) had elevated blood spot TSH (p less than 0.002) when the mothers had received an iodised oil injection during pregnancy. Most of the newborn (n = 18; 75%) of the latter group with elevated TSH (n = 24) came from mothers who had received the iodine injection only 1-25 days before delivery. Maternal iodine prophylaxis in late pregnancy does not increase the rate of neonatal hypothyroidism. CONCLUSIONS: It has been confirmed that severe iodine deficiency resulting in endemic goitre, cretinism, and hypothyroidism is prevalent in the regions studied. Dried blood spot TSH determinations may serve as an index for the efficiency of iodine prophylaxis programmes. Such a programme was carried out with relatively little expenditure and effort on a large scale basis.
Using two new immunoradiometric assays for thyrotropin, we measured thyrotropin levels in serum of patients suffering from various clinically and biochemically diagnosed thyroid disorders, and in healthy controls. A thyroliberin stimulation test was performed in all patients and controls. Thyrotropin levels were measured using a solid phase IRMA in 339 patients and a coated tube sandwich assay in 152 patients. The lower limits of detection of 0.1 mU/1 (solid phase IRMA) and 0.02 mU/1 (coated tube sandwich assay) as well as the specificity of these two assays were superior to those of conventional thyrotropin assays. Basal thyrotropin values were clearly different between euthyroid controls and patients non responding to thyroliberin stimulation. However, the values for these two groups overlapped those for patients showing a subnormal increase upon stimulation with thyroliberin. The thyroliberin stimulation test in patients with autonomous adenomas, together with the measurement of thyrotropin using these sensitive assays, provides additional information in the low range below 1.0 mU/1,i.e. below the lower limit of detection of conventional double antibody radioimmunoassays.
Human thyroglobulin (Tg) was isolated to apparent purity from various thyroid tissue samples obtained after surgery. Iodine and iodothyronine content of Tg was determined. Isoelectric focussing (IEF) was performed on thin layer agarose gels. Tg revealed a microheterogeneity of 6 bands in the range between pH 4.2 and 4.6. The intensity of the single bands depended on the iodothyronine content of Tg. With increasing degree of iodination, the bands with a lower pI (pI 4.35, 4.40) became more prominent, whereas the bands with higher pI (pI 4.55, 4.60) diminished. This typical change in microheterogeneity pattern could be confirmed by kinetic in vitro iodination and consecutive iodothyronine formation of low iodinated Tg (0.05% iodine). After in vitro desialylation, the bands shifted to a higher pH range (pH 4.60 to pH 4.90), but no reduction of the number of bands occurred. Even in desialylated Tg microheterogeneity is still dependent on iodine content. These results suggest, that the microheterogeneity of Tg is influenced, but not caused by different iodine and NANA content. Different polypeptide composition may be responsible for the microheterogeneity of Tg. In thyroid diseases without disturbance in Tg synthesis (endemic, diffuse and nodular goitre, Graves' disease) variations in relative intensity of single bands could be related to differences in iodine content. In thyroid cyst fluid and cold nodules in addition to low iodinated Tg, further bands were found with pI-values comparable to desialylated Tg.
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