The syndrome of generalized resistance to thyroid hormone is characterized by elevated circulating levels of thyroid hormone in the presence of an overall eumetabolic state and failure to respond normally to triiodothyronine. We have evaluated a family with inherited generalized resistance to thyroid hormone for abnormalities in the thyroid hormone nuclear receptors. A single guanine -* cytosine replacement in the codon for amino acid 340 resulted in a glycine --arginine substitution in the hormone-binding domain of one of two alleles of the patient's thyroid hormone nuclear receptor 13 gene. In vitro translation products of this mutant human thyroid hormone nuclear receptor (3 gene did not bind triiodothyronine. Thus, generalized resistance to thyroid hormone can result from expression of an abnormal thyroid hormone nuclear receptor molecule.
Subjects living in iodine deficient areas were reported to have elevated serum thyroglobulin (Tg) concentrations. This finding was interpreted as related to thyroid stimulation. Discrepant results, however, were found when serum Tg concentrations were correlated either with serum TSH or with goitre size. In this study we investigated the relationships between goitre size, serum Tg and serum TSH in 488 unselected adult subjects living in an endemic area of North-Western Tuscany (Garfagnana district). The control group comprised 352 subjects residing in a non-endemic area. In the endemic area a high prevalence of goitre was found (80.1%), thyroid enlargement being slight to moderate in the majority of cases and very large only in six subjects. Serum Tg concentrations increased and serum TSH levels decreased with the size of goitre. Statistical analysis by the chi-square cross correlation test showed that the converse changes of serum Tg and serum TSH in relation to goitre size were highly significant. These findings indicate that the increase of serum Tg occurring in endemic goitrous subjects may be related to factors other than TSH stimulation. Functional autonomy of the thyroid may account for the finding of low serum TSH and elevated serum Tg values in patients with large goitres. The present data do not exclude the possibility that the release of Tg is influenced by TSH stimulation, but indicate that other factors may be responsible for the increased levels of Tg found in endemic goitre.
The goitrogenic role of autoimmune phenomena in endemic goiter is still uncertain. Scanty and discrepant results have been reported in different areas of the world. This prompted us to evaluate the prevalence of circulating thyroid antibodies in an area of North-Western Tuscany during a survey for endemic goiter. The survey was carried out according to the P.A.H.O. criteria in a stable community. In all schoolchildren (n = 142, age range 7-15 yr) and in most of their parents (n = 159), thyroid size was evaluated and urine was collected for iodine determination. Blood was drawn for determination of circulating thyroid microsomal (MAb) and thyroglobulin antibodies (TgAb), TT3, TT4 and TSH. Prevalence of goiter in schoolchildren was 77.9% and 94.8% in their parents. Mean (+/- SD) urinary iodine excretion was 55.0 +/- 2.1 micrograms/24 h. The overall frequency of TgAb and MAb in the adult population was 14.4%, statistically higher than that of control subjects matched for sex and age. The frequency in schoolchildren was 4.3%. The presence of goiter in children was unrelated to the presence of thyroid antibodies in parents, whether goitrous or nongoitrous. A higher prevalence of goiter was found in children with goitrous parents as compared to children with nongoitrous parents (p less than 0.005). In conclusion, the frequency of thyroid autoantibodies in the adult population of the endemic area studied was increased, but showed no relation with the presence of goiter. The prevalence of goiter in children was associated with the presence of goiter but not of thyroid autoantibodies in parents. These data suggest that autoimmune phenomena are of limited importance in the development of endemic goiter.
The expression of the microsomal (M) antigen on the surface and in the cytoplasm of a strain of rat thyroid cells (FRTL-5) is under the regulation of TSH. In the present report the mechanism by which TSH induces such expression was investigated with the use of human microsomal antibody-positive serum and an indirect immunofluorescence technique. Studies were also performed to ascertain whether the M antigen of FRTL-5 cells could be identified with thyroid peroxidase (TPO), as suggested by recent data obtained in human thyroid tissue. Preabsorption experiments showed that, like solubilized human thyroid microsomes, purified human TPO completely abolished the binding of microsomal antibody to FRTL-5 cells. No inhibition was obtained by preabsorption with control human tissues (placenta, liver, and spleen) or human thyroglobulin, indicating that the antigen recognized by microsomal antibody in FRTL-5 cells was TPO. After 72 h of TSH withdrawal from the culture medium the M/TPO antigen disappeared from the surface and the cytoplasm of FRTL-5 cells. Readdition of TSH (250 microU/ml) to the culture medium of cells lacking the M/TPO antigen elicited its reappearance within 24-48 h. This effect of TSH was prevented by 10 microM cycloheximide or 0.5-5 micrograms/ml actinomycin D. Two well known stimulators of the adenylate cyclase-cAMP system, cholera toxin and forskolin, mimicked TSH in inducing the reappearance of the M/TPO antigen. A similar effect was observed with use of the phosphodiesterase inhibitor isobutylmethylxanthine. Reappearance of M/TPO antigen was also produced by the cAMP analog 8-bromo-cAMP. The tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate, which stimulates thyroid cell growth through a cAMP-independent pathway, was ineffective in inducing the M/TPO antigen in FRTL-5 cells. The present data indicate that 1) thyroid peroxidase accounts for most, if not all, of the microsomal antigen of FRTL-5 cells; and 2) TSH modulates the expression of the M/TPO antigen in FRTL-5 cells by a mechanism that involves cAMP production and requires mRNA formation and subsequent protein synthesis.
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