Two novel missense mutations in the thyroid peroxidase gene, R665W and G771R, result in a localization defect and cause congenital hypothyroidism.
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OBJECTIVE: Thyroid peroxidase (TPO) deficiency is one of the causes of thyroid dyshormonogenesis, because TPO plays a key role in thyroid hormone biosynthesis. To determine the frequency and pattern of TPO abnormalities, we have been screening TPO genes of patients with congenital goitrous hypothyroidism. SUBJECTS AND METHODS: TPO genes of a patient with congenital goitrous hypothyroidism and her parents were directly sequenced, and two novel missense mutations (R665W and G771R) were found. The former was derived from her father and the latter from her mother. R665 and G771 were well conserved in the peroxidase superfamily. When mRNAs containing each of the mutations were transfected into CHO-K1 cells, each cell showed faint TPO enzyme activity. However, immunofluorescence and immunoelectron microscopic analyses revealed that neither of the mutated TPOs reached the plasma membrane. CONCLUSIONS: Two novel missense mutations in the TPO gene were found. TPO proteins encoded by these mutated alleles showed abnormal cellular localization; namely, localization on the plasma membrane was disturbed. The loss of plasma membrane localization in mutated TPOs brought about the iodide organification defect, which was diagnosed as congenital hypothyroidism. (+info)
Epidemiological survey on the relationship between different iodine intakes and the prevalence of hyperthyroidism.
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OBJECTIVE: To investigate the effect of different levels of iodine intake on the prevalence of hyperthyroidism and the impact of universal salt iodization on the incidence of hyperthyroidism. DESIGN: A comparative cross-sectional and longitudinal survey was conducted in three areas with borderline iodine deficiency, mild iodine excess (previously mild iodine deficiency) and severe iodine excess. Universal salt iodization had been introduced 3 years previously except in the area with borderline iodine deficiency. METHODS: In total 16 287 inhabitants from three areas answered a questionnaire concerning the history of thyroid disease. Among them 3761 unselected subjects received further investigations including thyroid function, thyroid autoantibodies, thyroid ultrasonography and urinary iodine excretion. RESULTS: Among areas with median urinary iodine excretion of 103 microg/l, 375 microg/l and 615 microg/l (P<0.05), the prevalence of hyperthyroidism did not differ significantly (1.6%, 2% and 1.2%). The prevalence of subclinical hyperthyroidism was higher in areas with borderline iodine deficiency and mild iodine excess than in the area with severe excess iodine intake (3.7%, 3.9% and 1.1%, P<0.001). The prevalence of Graves' disease and its proportion in hyperthyroidism did not differ among areas. The incidence of hyperthyroidism did not significantly increase after the introduction of universal salt iodization. CONCLUSION: Different iodine intakes under a certain range do not affect the prevalence and type of hyperthyroidism. Subclinical hyperthyroidism is more prevalent in the iodine deficient area than in the severe iodine excessive area. In the area with mild iodine deficiency, the introduction of universal salt iodization may not be accompanied by an increased incidence of hyperthyroidism. (+info)
Intrauterine diagnosis and management of congenital goitrous hypothyroidism.
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The intrauterine recognition and treatment of congenital goitrous hypothyroidism may not only reduce the obstetric complications associated with large goiters, but possibly improve the prognosis for normal growth and mental development of affected fetuses. We present a case of fetal goiter diagnosed at 29 weeks of gestation following routine ultrasound examination. Fetal blood sampling performed at this time confirmed the presence of fetal hypothyroidism. Treatment was performed using a series of intra-amniotic injections between 31 and 36 weeks, initially with tri-iodothyronine (T3) and subsequently with thyroxine. During this period, shrinkage of the fetal goiter, increasing neck flexion and resolution of the polyhydramnios was observed. Following birth, neonatal serum thyroid-stimulating hormone levels were within the normal range but thyroxine was reduced. The baby was started on daily oral thyroxine and, on examination 7 weeks following birth, he appeared clinically and chemically euthyroid. In the absence of maternal thyroid disease, fetal goiter is extremely rare, with only seven cases previously reported in the English literature to have used intra-amniotic thyroxine injections as a form of treatment. This report reviews the current literature regarding the diagnosis and intrauterine management of fetal goiter and considers the possibility of T3 therapy in future cases of congenital hypothyroidism. (+info)
Antenatal diagnosis and treatment of a case of fetal goitrous hypothyroidism associated with high-output cardiac failure.
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A case of fetal goitrous hypothyroidism associated with high-output cardiac failure is presented. At 32 weeks of gestation, the antenatal diagnosis of goiter was made based on ultrasound examination, and the fetal thyroid function was examined by amniocentesis and cordocentesis. Color and pulsed Doppler examinations demonstrated a high vascular flow pattern in the goiter and marked elevation of the maximum velocity in the common carotid artery at the level of the neck. It was suspected that arteriovenous shunting through the large goiter resulted in high-output cardiac failure with cardiomegaly and pleural effusion. The fetus was treated by injection of levothyroxine sodium into the amniotic fluid at 33 weeks of gestation and the goiter thereafter decreased in size, with subsequent improvement of the high-output cardiac failure. The maximum velocity in the common carotid artery fell rapidly before the shrinkage of the fetal goiter and in parallel with the fetal level of thyroid stimulating hormone. (+info)
Radioimmunoassay for estimation of thyroglobulin in human serum.
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A specific double antibody radioimmunoassay has been develop for the measurement of thyroglobulin in human serum. Human thyroglobulin was purified by combined DEAE-cellulose and affinity chromatography using Sepharose 4B-bound Concanavalin A. Sensitivity of test serum was 10 ng/ml. Thyroglobulin was not detectable in half of normal subjects, and half showed values between 10 and 180 ng/ml. In the patients with simple goiter and secondary hypothyroidism, serum thyroglobulin was usually in the normal range. In Hashimoto's thyroiditis, many sera having precipitating antibodies or high hemagglutination antibodies for thyroglobulin showed a high thyroglobulin concentration in serum probably due to a false positive reaction. In hyperthyroidism, an increased thyroglobulin level was observed in 64% of patients. However, there was no correlation between serum thyroglobulin and thyroxine levels in untreated hyperthyroidism. Serum thyroglobulin was increased significantly in some cases for several weeks after isotope therapy for the hyperthyroidism. (+info)
Goitrogenic and estrogenic activity of soy isoflavones.
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Soy is known to produce estrogenic isoflavones. Here, we briefly review the evidence for binding of isoflavones to the estrogen receptor, in vivo estrogenicity and developmental toxicity, and estrogen developmental carcinogenesis in rats. Genistein, the major soy isoflavone, also has a frank estrogenic effect in women. We then focus on evidence from animal and human studies suggesting a link between soy consumption and goiter, an activity independent of estrogenicity. Iodine deficiency greatly increases soy antithyroid effects, whereas iodine supplementation is protective. Thus, soy effects on the thyroid involve the critical relationship between iodine status and thyroid function. In rats consuming genistein-fortified diets, genistein was measured in the thyroid at levels that produced dose-dependent and significant inactivation of rat and human thyroid peroxidase (TPO) in vitro. Furthermore, rat TPO activity was dose-dependently reduced by up to 80%. Although these effects are clear and reproducible, other measures of thyroid function in vivo (serum levels of triiodothyronine, thyroxine, and thyroid-stimulating hormone; thyroid weight; and thyroid histopathology) were all normal. Additional factors appear necessary for soy to cause overt thyroid toxicity. These clearly include iodine deficiency but may also include additional soy components, other defects of hormone synthesis, or additional goitrogenic dietary factors. Although safety testing of natural products, including soy products, is not required, the possibility that widely consumed soy products may cause harm in the human population via either or both estrogenic and goitrogenic activities is of concern. Rigorous, high-quality experimental and human research into soy toxicity is the best way to address these concerns. Similar studies in wildlife populations are also appropriate. (+info)
Thyroid follicular cells secrete plasminogen activators and can form angiostatin from plasminogen.
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Angiostatin, a 38 kDa fragment of plasminogen, potently inhibits the growth of blood vessels. Angiostatin is generated from plasminogen by urokinase-type (uPA) and tissue-type (tPA) plasminogen activators in the presence of free sulphydryl donors. Angiogenesis inhibitors may be important in regulating angiogenesis in developing goitre. We have examined angiostatin formation in human primary thyrocyte cultures and a rat thyrocyte cell line (FRTL-5). We found that human thyroid cells in culture secrete plasminogen activators (both tPA and uPA) as well as matrix metalloproteinase 2 into the medium. When human thyrocyte conditioned medium was incubated with plasminogen (10 microg/ml) and N-acetylcysteine (100 microM) for 24 h, a 38 kDa fragment of plasminogen, which is consistent with angiostatin, was generated. The appearance of the 38 kDa fragment was increased by agents that increase cAMP (forskolin and 8 BrcAMP). FRTL-5 cells, which do not secrete uPA or tPA, did not generate angiostatin. Thyroid cells produce several angiogenic growth factors, and human thyrocyte conditioned medium stimulated growth of endothelial cells. When the conditioned medium was incubated with plasminogen and N-acetylcysteine, this stimulatory effect was lost, consistent with the production of a growth inhibitory factor. We conclude that thyroid cells can produce angiostatin from plasminogen in vitro, and this may play a role in vivo in limiting goitre size. (+info)
Controversies in radioiodine therapy: relation to ophthalmopathy, the possible radioprotective effect of antithyroid drugs, and use in large goitres.
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In routine use for more than 50 years, radioiodine ((131)I) is generally considered safe and devoid of major side effects. Therefore, it is surprising that relatively many aspects of radioiodine therapy are controversial, as illustrated by recent international questionnaire studies. Our review aims at highlighting three of these areas - namely, the influence of (131)I on the course of Graves' ophthalmopathy, the possible radioprotective effects of antithyroid drugs, and the use of (131)I in large goitres. (131)I therapy carries a small (but definite) risk of causing progression of Graves' ophthalmopathy. Identification of risk factors (thyroid dysfunction, high level of thyroid-stimulating hormone (TSH) receptor antibodies, cigarette smoking) allows the identification of patients at risk and the institution of concomitant glucocorticoid treatment, thereby hindering progression of eye disease. On the basis, largely, of retrospective data, it appears that carbimazole (or methimazole), if stopped 3-5 days before treatment, does not influence the outcome of (131)I therapy. Simultaneous thyrostatic medication most probably reduces the efficacy of (131)I, as does restarting it within 7 days. Propylthiouracil seems to have a more prolonged radioprotective effect than carbimazole. Surgery is the treatment of first choice in patients with a large goitre. However, in the case of patient ineligibility or preference, (131)I therapy may be an option. The treatment has a favourable effect on tracheal compression and inspiratory capacity, but the reduction in thyroid volume is only 30-40%. Inpatient treatment, necessitated by the large doses, makes the treatment cumbersome. Controversy related to radioiodine therapy is mainly based on the lack of adequate prospective randomised studies comparing efficacy, side effects, cost and patient satisfaction. (+info)