triiodothyronine--reverse and Congenital-Hypothyroidism

Topics: Canada; Congenital Hypothyroidism; Fetal Blood; Humans; Hypothyroidism; Infant, Newborn; Infant, Newborn, Diseases; Mass Screening; Radioimmunoassay; Thyroid Function Tests; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse; United States

Thyroid hormones are essential for a variety of developmental and metabolic processes. Congenital hypothyroidism (CHT) results in severe defects in the development of different tissues, in particular brain. As an animal model for CHT, we studied Pax8(-/-) mice, which are born without a thyroid gland. We determined the expression of iodothyronine deiodinase D1 in liver and kidney, D2 in brain and pituitary, and D3 in brain, as well as serum T(4), T(3), and rT(3) levels in Pax8(-/-) vs. control mice during the first 3 wk of life. In control mice, serum T(4) and T(3) were undetectable on the day of birth (d 0) and increased to maximum levels on d 15. In Pax8(-/-) mice, serum T(4) and T(3) remained below detection limits. Serum rT(3) was high on d 0 in both groups and rapidly decreased in Pax8(-/-), but not in control mice. Hepatic and renal D1 activities and mRNA levels were low on d 0 and increased in control mice roughly parallel to serum T(4) and T(3) levels. In Pax8(-/-) mice, tissue D1 activities and mRNA levels remained low. Cerebral D2 activities were low on d 0 and increased to maximum levels on d 15, which were approximately 10-fold higher in Pax8(-/-) than in control mice. D2 mRNA levels were higher in Pax8(-/-) than in control mice only on d 21. Cerebral D3 activities and mRNA levels were high on d 0 and showed a moderate decrease between d 3 and 15, with values slightly lower in Pax8(-/-) than in control mice. One day after the injection of 200 ng T(4) or 20 ng T(3)/g body weight, tissue deiodinase activities and mRNA levels were at least partially restored toward control levels, with the exception of cerebral D3 activity. In conclusion, these findings show dramatic age and thyroid state-dependent changes in the expression of deiodinases in central and peripheral tissues of mice during the first 3 wk of life.

Topics: Aging; Animals; Brain; Congenital Hypothyroidism; Disease Models, Animal; DNA-Binding Proteins; Female; Gene Expression Regulation, Enzymologic; Growth Disorders; Hypothyroidism; Iodide Peroxidase; Kidney; Liver; Male; Mice; Mice, Knockout; Nuclear Proteins; Paired Box Transcription Factors; PAX8 Transcription Factor; Pituitary Gland; RNA, Messenger; Thyroxine; Trans-Activators; Triiodothyronine; Triiodothyronine, Reverse

Compared with euthyroid controls, patients with congenital hypothyroidism (CH) who are receiving L-T(4) treatment show elevated serum TSH relative to serum T(4) concentrations and increased T(4)/T(3) ratio. These abnormalities could be the consequence of impaired activity of the selenoenzymes deiodinases on which patients with CH rely to convert the ingested L-T(4) into active T(3). Eighteen patients (0.5-15.4 yr), diagnosed with CH in infancy, received selenomethionine (SeM, 20-60 microg selenium/day) for 3 months. The study took place in Belgium, a country where selenium intake is borderline. Compared with the values observed in age- and sex-matched euthyroid controls, patients with CH had decreased selenium, thyroglobulin and T(3) concentrations and increased TSH, reverse T(3), and T(4) concentrations and T(4)/T(3) ratio at baseline. Selenium supplementation caused a 74% increase in plasma selenium values but did not affect the activity of the selenoenzyme glutathione peroxidase used as a marker of selenium status. SeM abolished the TSH difference observed between CH patients and euthyroid controls at baseline and caused a significant decrease in thyroglobulin values. Thyroid hormone concentrations were not affected by SeM. In conclusion, our data suggest that selenium is not a limiting factor for peripheral T(4)-to-T(3) conversion in CH patients. In contrast, we find indirect evidence that SeM improves thyroid hormones feedback at the hypothalamo-pituitary level and decreases stimulation of the residual thyroid tissue, possibly suggesting greater intracellular T(4)-to-T(3) conversion.

Topics: Adolescent; Child; Child, Preschool; Congenital Hypothyroidism; Dietary Supplements; Glutathione Peroxidase; Humans; Hypothyroidism; Infant; Selenium; Selenomethionine; Thyroglobulin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The plasma levels of thyroxine (T4), triiodothyronine (T3), free T4 (FT4), free T3 (FT3), reverse T3 (rT3) and immunoradiometrically assayed thyrotropin (IRMA TSH) have been measured in 28 L-T4-treated children with congenital hypothyroidism as well as in a control group (group C). The patients were subdivided into 2 groups according to the nonsuppressed (group A) or suppressed (group B) TSH response to TSH-releasing hormone (TRH). Basal IRMA TSH correlated with the TSH increment after TRH and it was significantly lower in group B vs. groups A and C, while no difference was present between groups A and B in regard to T4, FT4 and rT3, all higher than in group C. FT3 levels were similar in the 3 groups. In children, as in adults, basal IRMA TSH seems to be a reliable index in monitoring overtreatment.

Topics: Adolescent; Child; Child, Preschool; Congenital Hypothyroidism; Female; Humans; Hypothyroidism; Male; Radioimmunoassay; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

In five L-thyroxine-substituted hypothyroid children with partial epilepsy serum total thyroxine (T4) and free T4 (FT4) significantly (P less than 0.01) decreased following 2 months of carbamazepine (CBZ) administration (20 mg/kg per BW per day) from mean (+/- SD) values of 12.7 +/- 1.1 micrograms/dl and 15.5 +/- 1.8 pg/ml to mean values of 7.5 +/- 2.3 and 10.1 +/- 1.7, respectively. In all but one patient important changes in both serum total and free triiodothyronine (T3, FT3) were not observed; consequently T3:T4 and FT3:FT4 ratios significantly (P less than 0.05) increased in the whole series. Three subjects had post-treatment serum TSH that rose to hypothyroid levels parallel to a T4 decrease. The negligible thyroid hormone secretion and the unmodified T3-uptake (T3U) or T4-binding globulin (TBG) exclude direct effects of CBZ on thyroid gland and on carrier serum proteins, respectively. The findings observed, instead, might be due to accelerated T4 metabolic clearance together with augmented T4 to T3 conversion rate, as previously demonstrated for diphenylhydantoin. The sharp reduction in T4 and FT3 concentrations is the peripheral display of this event, which is associated with a decompensation of the metabolic status, as indicated by serum TSH enhancement. In all cases a supplement of L-thyroxine by itself was able to restore euthyroid TSH serum concentrations, suggesting that hypothyroidism in patients with partial epilepsy to whom CBZ had been administered requires a higher L-T4 substitutive regimen.

Topics: Carbamazepine; Child; Child, Preschool; Congenital Hypothyroidism; Epilepsies, Partial; Female; Humans; Hypothyroidism; Male; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Time Factors; Triiodothyronine; Triiodothyronine, Reverse

Well-preserved thyroid glands from 28 fetuses 22-34 weeks of gestational age and from 4 term newborns who survived at most 12 days were examined to study thyroid development in late intrauterine life. Total iodine thyroglobulin (Tg), T4, T3 and rT3 were assayed before and after hydrolysis with pronase. In the same maternity unit the cord-serum of 25 healthy term newborns was also assayed and the urine iodine on the day of delivery was tested in 52 newborns and their mothers. Results are expressed as mean values +/- SD. The thyroid gland weight ratio to body weight for the preterms was 0.063 +/- 0.024; thyroid Tg content 5.9 +/- 4.0 mg/g; total thyroid iodine 41.7 +/- 35.1 micrograms/g; Tg iodination 0.72 +/- 0.37%; hormone quota of Tg iodine 39.9 +/- 12.4. Molar ratios were: T4/Tg 3.3 +/- 1.6, T3/Tg 0.25 +/- 0.14, rT3/Tg 0.072 +/- 0.059. Considerable differences in thyroid iodine content and Tg iodination were observed although the availability of iodine was presumably the same. The high Tg iodination reflects the enhanced uptake of the fetal thyroid. The quantity of iodine involved in hormonogenesis varied greatly among fetuses of the same gestational age, this being in the third term as active as in fully mature thyroids. Hormonogenesis seemed preferentially directed to production of T4 and rT3, which, in the latter case, is higher peripherically. Four preterms with a particularly low level of hormonogenesis were not seen to have deficient levels of thyroid iodine or Tg iodination and the most compromised step was the iodine utilization in the production of hormones.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Congenital Hypothyroidism; Female; Fetus; Gestational Age; Humans; Infant, Newborn; Iodine; Male; Organ Size; Thyroglobulin; Thyroid Gland; Thyroid Hormones; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The concentrations of T4, T3, r-T3, TSH and Tg were determined in parallel in maternal serum at the time of delivery and in cord blood. The serum T3 concentration in cord blood was significantly lower than that in the serum of the mother. However contrary to T3, r-T3 in cord serum was significantly higher than in maternal serum. Also, the level of TSH in cord blood was considerably higher than in maternal serum. The concentrations of total T4 in maternal and cord serum did not differ markedly, even though the values (mean and individual) were somewhat lower in the cord serum. The concentrations of Tg in cord and maternal serum varied widely, although the mean value for Tg in cord serum was somewhat higher than in maternal serum. No correlation was found between Tg concentration and TSH level in cord or maternal serum.

Topics: Congenital Hypothyroidism; Female; Fetal Blood; Humans; Labor, Obstetric; Pregnancy; Thyroglobulin; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

A pilot study was performed to establish optimal conditions for nation-wide screening for congenital hypothyroidism in Sweden. The levels of T4 and TSH were determined by automated radioimmunoassay in the dried blood spots, routinely collected for PKU screening on the fifth postnatal day, from all 19 792 infants born in the Stockholm area during a 14-month period. To identify safe minimum recall criteria for routine use, infants were recalled if the TSH level was more than 30 mU/l of plasma or--if they were not preterm--the T4 concentration was less than -2 S.D. of the mean. Altogether 160 infants were recalled. Seven newborns with congenital hypothyroidism were identified, 6 with primary and one with secondary hypothyroidism. Five infants had decreased levels of thyroxine-binding globulin. The results of the follow-up analyses from recalled infants showed that determination of the reverse-T3 level may be of diagnostic value around the 23rd day of life. The results of the clinical investigation of recalled infants are reported in a subsequent paper and a programme for nation-wide screening for congenital hypothyroidism is proposed.

Topics: Congenital Hypothyroidism; Follow-Up Studies; Humans; Hypothyroidism; Infant, Newborn; Mass Screening; Phenylketonurias; Pilot Projects; Radioimmunoassay; Sweden; Thyrotropin; Thyroxine; Triiodothyronine, Reverse

A new sensitive radioimmunoassay method for measuring reverse triiodothyronine (rT3) concentrations in dried blood samples, designed to screen newborn infants for congenital hypothyroidism, has been developed. Paper strips are impregnated with cord blood and dried. Duplicate 5-mm diameter discs are punched from the paper strips and added directly to the radioimmunoassay reaction mixture. After incubation, bound and free hormone are separated by dextran-coated charcoal. The disc remains in the solution throughout the procedure and the assay can be completed within 24 hr. Recovery of rT3 is greater than 95% and coefficients of variation are 9.4% (intraassay) and 12.2% (interassay) at an rT3 concentration of 220 ng/dl. At very low rT3 concentrations (25 ng/dl), coefficients of variation are 14.2% (intraassay) and 18.7% (interassay). The method readily detects 12.5 ng/dl of rT3. With this paper disc method, rT3 was measured in 38 newborns and compared with serum rT3 measured in the same subjects by a standard radioimmunoassay method. The correlation between rT3 values measured in dried blood disc and in serum was very high (r = 0.918). The rT3 in dried blood discs from the cord blood of 745 normal newborns was 228.9 +/- 76.0 ng/dl (mean +/- SD). In contrast, two infants with proven congenital hypothyroidism had rT3 values of 35 and 75 ng/dl, respectively. This study indicates that rT3 can be easily measured in dried blood discs and suggests that the described method may be a useful screening procedure in a program for the detection of neonatal hypothyroidism.

Topics: Congenital Hypothyroidism; Fetal Blood; Humans; Hypothyroidism; Infant, Newborn; Infant, Newborn, Diseases; Paper; Radioimmunoassay; Statistics as Topic; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Amniotic fluid rT3 levels were measured during pregnancy in two women who previously gave birth to infants suffering from neonatal hypothyroidism. In the first case, hypothyroidism was strongly suspected because of repeated low levels of rT3 in the amniotic fluid (20-64 ng/dl) at 16 and 31 weeks of gestation. A normal infant was delivered. He is now 10 months old and taking no treatment; he has no clinical or laboratory signs of hypothyroidism. In the second case, amniotic rT3 levels (140-180 ng/dl) were well within the normal range for 15-19 weeks of pregnancy, but an affected hypothyroid infant was born. These data suggest that amniotic fluid rT3 levels may not be a reliable tool in diagnosing intrauterine hypothyroidism.

Topics: Adult; Amniotic Fluid; Congenital Hypothyroidism; Female; Gestational Age; Humans; Hypothyroidism; Infant, Newborn; Male; Prenatal Diagnosis; Triiodothyronine; Triiodothyronine, Reverse

Topics: Cell Migration Inhibition; Congenital Hypothyroidism; Diagnosis, Differential; Electrophoresis; Humans; Thyroid Diseases; Triiodothyronine, Reverse

Topics: Congenital Hypothyroidism; Female; Humans; Hypothyroidism; Infant; Infant, Newborn; Male; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The thyroid function of patients with three different types of organification defect was studied. All patients were characterized by a high thyroidal 131I uptake and a positive perchlorate discharge. Patients with Pendred's syndrome who had goitre and congenital nerve deafness were mostly euthyroid with normal circulating thyroid hormone levels. Only two of them had compensated euthyroidism with elevated total T3, high basal TSH and delayed return to basal value with TRH. The patients who were euthyroid with large goitres and normal hearing had elevated total T3 and an exaggerated TSH response to TRH. The thyroid function of these two groups of patients contrasted with that of goitrous cretins, who were clinically hypothyroid with low circulating total T4, increased T3 and decreased rT3 levels. The data suggest that in patients with intrathyroidal iodine deficiency secondary to organification defect, there is preferential T3 production in an effort to maintain euthyroid state, and this is further substantiated in the case of gross thyroid insufficiency either by enhanced peripheral conversion of T4 to T3, or reduced metabolic clearance of T3 and increased clearance of rT3, resulting in elevated T3 and decreased rT3 levels.

Topics: Adolescent; Adult; Congenital Hypothyroidism; Deafness; Female; Goiter; Humans; Iodine; Male; Pedigree; Syndrome; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Reverse triiodothyronine (rT3) was measured in cord serum from 5 infants with congenital hypothyroidism and compared with normal values in 70 euthyroid control infants. The mean (and SEM) value in the affected infants (135 +/- 12 ng/dl) was significantly lower than that in the control population (270 +/- 9 ng/dl). However, the large overlap in range of concentrations in affected and control infants indicates that newborn screening based on the determination of rT3 in cord blood specimens offers no advantage over present screening methods.

Topics: Congenital Hypothyroidism; Fetal Blood; Humans; Hypothyroidism; Infant, Newborn; Triiodothyronine; Triiodothyronine, Reverse

Topics: Congenital Hypothyroidism; False Negative Reactions; False Positive Reactions; Fetal Blood; Gestational Age; Humans; Hypothyroidism; Infant, Newborn; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse