Hypothyroid Newborns Research Articles

Thyroid Function in Mothers of Hypothyroid Newborns

Thyroid Function in Mothers of Hypothyroid Newborns

Rapid and Automated Assay for Thyrotropin in Guthrie Cards on the ACS:180

Congenital hypothyroidism causes a decreased growth rate and skeletal development and can lead to severe mental retardation (1). In the nearly three decades since measurement of thyroxine in filter paper dried blood disks (Guthrie cards) was introduced as a method to screen newborns for congenital hypothyroidism (2), new procedures for thyroxine and thyrotropin (TSH), such as ELISA, fluoroimmunoassay, or chemiluminescence (3) have been developed or adapted from commercial kits, most of them requiring overnight incubation. Previously, we described a manual adaptation of a commercial immunochemiluminometric assay kit based on an acridinium label to measure TSH in dried blood spots (4). This method is used routinely in our laboratory, and we have detected 176 congenital hypothyroidism cases in the 480 000 newborn samples tested. Studies concerning its correlation with the DELFIATM neonatal TSH kit (Wallac Oy) were also described (5). Here, we present results obtained with a rapid and automated third-generation TSH chemiluminescent assay for serum samples adapted to measure TSH in Guthrie cards (ACS:180TM, Chiron Diagnostics). This fully automated chemiluminescence immunoassay system uses paramagnetic particles as the solid phase (6). We measured TSH in 2200 dried blood spot samples obtained in filter paper (Schleicher and Schuell, cat. no. 903) by heel stick from newborns routinely referred to our service. The samples were dried at room temperature, and the TSH concentrations were measured using our routine chemiluminescent method (4) and also by the technique described here. We used calibrators at 2.2, 22.0, 55.0, 110.0, 220.0, and 550.0 mIU TSH/L serum equivalent and controls at 33.0 and 132.0 mIU TSH/L serum equivalent provided with the DELFIA …

A single amino acid change in the acetylcholinesterase-like domain of thyroglobulin causes congenital goiter with hypothyroidism in the cog/cog mouse: a model of human endoplasmic reticulum storage diseases.

Newly synthesized thyroglobulin (Tg), the major secretory glycoprotein of the thyroid gland, folds and homodimerizes in the endoplasmic reticulum (ER) before its export to the site of iodination, where it serves as the precursor for thyroid hormone synthesis. In families with defective Tg export, affected individuals suffer from a thyroidal ER storage disease characterized by a distended thyrocyte ER containing misfolded Tg, along with induced ER molecular chaperones. Inherited as an autosomal recessive trait, deficient Tg causes congenital hypothyroidism in newborns that, if untreated, results in goiter along with serious cognitive and growth defects. Recently, a similar phenotype has been observed in inbred cog/cog mice, although the precise molecular defect has remained undefined. Here, we have isolated and cloned a full-length 8.5-kb Tg cDNA from cog/cog mice and unaffected isogenic AKR/J mice. Comparison of the complete sequences reveals that cog/cog mice express a Leu-2263 --> Pro missense mutation in the acetylcholinesterase-homology domain of Tg. Heterologous expression studies in COS cells indicate that cog Tg exhibits a severe defect in exit from the ER. Site-directed mutagenesis of cog Tg to convert the single amino acid back to Leu-2263 restores normal Tg secretion. We conclude that the cog mutation in Tg is responsible for this ER storage disease that causes thyroid dyshormonogenesis.

Heelprick testing of neonates: the role of the midwife

Screening of newborns for phenylketonuria and congenital hypothyroidism can prevent brain damage and severe intellectual impairment from these conditions. The success of the national programme relies heavily on the input of midwives. This paper reviews the screening programme, with particular emphasis on the stages at which midwives are involved, drawing on the findings of the recent national audit of the programme.

Measurement of urinary iodine excretion to reveal iodine excess in neonatal transient hypothyroidism.

This study was undertaken to confirm the importance of iodine excess in neonatal transient hypothyroidism. In 30 transient hypothyroid newborns at screening we measured urinary iodine excretion and TSH. They were divided into two groups: group A consisted of 21 newborns who had been exposed to iodine; group B of 9 non-exposed newborns. The two groups were significantly different only for median urinary iodine excretion (p = 0.001). In 61.5% of newborns of group A, iodine exposure caused iodine excess (urinary iodine excretion higher than 185 micrograms/l); this correlated with a higher prevalence of prematurity and a lower mean gestational age. Clinical records should reveal iodine exposure, but only urinary iodine excretion shows iodine excess. We suggest that evaluation at birth of urinary iodine excretion in every newborn with high TSH could help in predicting a good prognosis, since hypothyroidism due to the Wolff-Chaikoff effect is always spontaneously reversible, even if treatment may be suggested.

Thyroid Hormones Regulate the Onset of Osmotic Activity of Rat Liver Mitochondria after Birth*

The effect of thyroid hormone deprivation on the osmotic activity of liver mitochondria from early newborn rats was studied. Experimentally induced hypothyroidism prevented the increase in the osmotic activity of mitochondria observed immediately after birth. Osmotic activity was restored by T4 and T3 treatment to hypothyroid newborns but not when this treatment was supplemented with cycloheximide. Under the same circumstances, streptomycin had no effect. Hypothyroidism abolished the change in the slope of the osmotic curve (plot of inverse absorbance of mitochondrial suspensions incubated in sucrose solutions vs. inverse sucrose concentration) observed in mitochondria from euthyroid newborns at 110-120 mOsm sucrose, suggesting that hypothyroidism prevents the formation of tight physical connections between mitochondrial outer and inner membranes. Thyroid hormone deprivation increased the passive permeability of the mitochondrial inner membrane to protons, resulting in a decreased respiratory control ratio. Hypothyroidism prevented the sharp decrease in the affinity of mitochondria for ATP observed in euthyroid newborns immediately after birth. These results corroborate our previous suggestion (Endocrinology, 1995, 136:4448) that, during the early neonatal period, thyroid hormones control the synthesis of some nucleus-coded protein(s) involved in the assembly of F0,F1-ATPase.

Thyroid Hormones Regulate the Onset of Osmotic Activity of Rat Liver Mitochondria after Birth

The effect of thyroid hormone deprivation on the osmotic activity of liver mitochondria from early newborn rats was studied. Experimentally induced hypothyroidism prevented the increase in the osmotic activity of mitochondria observed immediately after birth. Osmotic activity was restored by T4 and T3 treatment to hypothyroid newborns but not when this treatment was supplemented with cycloheximide. Under the same circumstances, streptomycin had no effect. Hypothyroidism abolished the change in the slope of the osmotic curve (plot of inverse absorbance of mitochondrial suspensions incubated in sucrose solutions vs. inverse sucrose concentration) observed in mitochondria from euthyroid newborns at 110–120 mOsm sucrose, suggesting that hypothyroidism prevents the formation of tight physical connections between mitochondrial outer and inner membranes. Thyroid hormone deprivation increased the passive permeability of the mitochondrial inner membrane to protons, resulting in a decreased respiratory control ratio. Hypothyroidism prevented the sharp decrease in the affinity of mitochondria for ATP observed in euthyroid newborns immediately after birth. These results corroborate our previous suggestion that, during the early neonatal period, thyroid hormones control the synthesis of some nucleus-coded protein(s) involved in the assembly of F0,F1-ATPase.

Type II and type III deiodinase activity in human placenta as a function of gestational age.

Thyroid hormones are essential for fetal development. T4 can be activated by type I (ID-I) and type II (ID-II) iodothyronine deiodinase or inactivated by type III deiodinase (ID-III). The influence of placental ID-II and ID-III on the regulation of fetal thyroid hormone levels was investigated. Using [125I]T4 and [125I]T3, respectively, ID-II and ID-III activities were measured in homogenates of normal human placentas from 6-43 weeks gestational age and in placentas from five term neonates with a total thyroid hormone synthesis defect. ID-II and ID-III activities related to protein or DNA concentration decreased and total placental ID-III activity increased significantly during pregnancy, whereas the increase in total placental ID-II activity was not significant. Absolute placental ID-II activity was approximately 200 times lower than ID-III activity at all gestational ages. Therefore, fluctuations in ID-II activity were not likely to have a significant influence on fetal thyroid hormone concentrations, but may play a role in the regulation of intraplacental T3 generation. The high ID-III activity most likely influences the thyroid hormone economy of the fetus. Severely hypothyroid newborns showed strongly decreased serum T4 levels, but serum T3 and placental ID-III activities were similar to those in euthyroid newborns. These results suggest that placental ID-III activity is regulated by serum T3, but not by serum T4.

Treatment Guidelines for Hyperthyroidism and Hypothyroidism

To the Editor. —The article by Dr Singer and colleagues 1 fails to discuss the treatment of congenital hypothyroidism diagnosed and treated in the newborn period. Because of almost universal screening for this condition, this omission is serious. Physicians treating hypothyroid newborns with the 4-μg/kg dose of levothyroxine recommended for children (on page 811 of the article) would be undertreating their patients. Such a dose is fine for a 6-year-old child with acquired disease, but not for a newborn in whom 8 to 10 μg/kg would be a more appropriate starting dose.

Hypothyroidism prevents postnatal changes in rat liver mitochondrial populations defined by rhodamine-123 staining.

The effect of hypothyroidism on the percentages of low fluorescence population (LFP) and high fluorescence population (HFP) rhodamine-123-stained mitochondria, respiratory parameters, and ATPase activity were studied in liver mitochondria from early newborn rats. Hypothyroidism prevented the decrease in the percentage of HFP and the subsequent increase in LFP that occurs immediately after birth. This effect coincides with the impairment of mitochondrial respiratory function, as shown by the low respiratory control ratio and the low activity of F0,F1-ATPase found in hypothyroid newborns. All of these changes were reversed by the administration of thyroid hormones. ATP in vitro promotes the conversion of HFP into LFP and increases the respiratory control ratio in hypothyroid newborns, although this effect was not observed after thyroid hormone treatment. The effect of thyroid hormones on both the postnatal changes in mitochondrial populations and in F0,F1-ATPase activity was prevented by cycloheximide, but not by streptomycin. Thus, the observed effects of thyroid hormones on neonatal mitochondria must be accomplished by the induction of the synthesis of some nuclei-coded protein, possibly involved in F0,F1-ATPase assembly.

Hypothyroidism prevents postnatal changes in rat liver mitochondrial populations defined by rhodamine-123 staining

The effect of hypothyroidism on the percentages of low fluorescence population (LFP) and high fluorescence population (HFP) rhodamine-123-stained mitochondria, respiratory parameters, and ATPase activity were studied in liver mitochondria from early newborn rats. Hypothyroidism prevented the decrease in the percentage of HFP and the subsequent increase in LFP that occurs immediately after birth. This effect coincides with the impairment of mitochondrial respiratory function, as shown by the low respiratory control ratio and the low activity of F0,F1-ATPase found in hypothyroid newborns. All of these changes were reversed by the administration of thyroid hormones. ATP in vitro promotes the conversion of HFP into LFP and increases the respiratory control ratio in hypothyroid newborns, although this effect was not observed after thyroid hormone treatment. The effect of thyroid hormones on both the postnatal changes in mitochondrial populations and in F0,F1-ATPase activity was prevented by cycloheximide, but not by streptomycin. Thus, the observed effects of thyroid hormones on neonatal mitochondria must be accomplished by the induction of the synthesis of some nuclei-coded protein, possibly involved in F0,F1-ATPase assembly.

Audiological Assessment of Eleven Congenital Hypothyroid Infants Before and After Treatment

Eleven congenital hypothyroid newborns were consecutively referred for audiological evaluation before any treatment. Evoked otoacoustic emissions were present bilaterally in 9 newborns. These results suggest the normality outer hair cells and contrast with results obtained in experimental studies. The auditory brainstem responses in 6 newborns showed a prolonged wave I, as previously reported by other authors. At 9 to 12 months of age, all children treated had evoked otoacoustic emissions in at least one ear. In 9 cases, the auditory threshold was normal (equal to or below 20 dB) as determined by behavioural tests.

Developmental changes in ventricular action potential properties in guinea-pigs are modulated by age-related changes in the thyroid state

Previous studies have demonstrated that in different cardiac preparations action potential duration (APD) increases with age. As in various species, thyroid hormone levels increase developmentally, and since hyperthyroidism shortens APD while hypothyroidism prolongs it, we hypothesized that developmental changes in APD result from age-related variations in the thyroid state. The hypothesis was tested by analysing ventricular action potentials and total T 4 (TT 4) levels in guinea-pigs in the age range of 0 days to 3 months (adult), and in hyperthyroid and hypothyroid newborns (0–5 days old). We found that APD 50 increased exponentially with age with a time constant of 6.7 days, from 100.6 ± 3.4 ms in newborns (0–5 days old) to 147.4 ± 5.2 ms in adults ( P<0.001). TT 4 decreased exponentially with age with a time constant of 4.8 days, from 3.9 ± 0.4 μg/dl in newborns to <1.0 μg/dl in adults. In the age range studied, APD 50 and TT 4 were linearly correlated: Y = −12.13X + 142, r − 0.865. In contrast to the marked changes in APD, resting potential and action potential amplitude were age-independent, and V ̇ max only slightly increased with age. Alterations in the thyroid state in newborns affected ventricular action potentials as predicted by the hypothesis. In euthyroid (TT 4 = 3.9 ± 0.4 μg/dl), hypothyroid (TT 4 = 1.6 ± 0.4 μg/dl) and hyperthyroid (TT 4 = 39.8 ± 10.8 μg/dl) newborns, APD 50 was: 100.6 ± 3.4 ms, 117.7 ± 4.2 ∗ ms,and 63.7 ± 7.4 ∗ ms, respectively ( ∗ P<0.01). The findings of this study suggest that the age-related alterations in the thyroid state may be responsible for the developmental changes in ventricular action potential duration.

Role of Thyroid State in Age-Dependent Cardiac Effects of Ouabain in Guinea Pigs

We tested the hypothesis that the decrease in the thyroid state, with age, contributes to the age-related increase in myocardial responsiveness to cardiac glycosides. Thyroid hormone levels (reflecting the thyroid state): total T4 (microgram/dl) and total T3 (ng/dl) in the 3 groups of guinea pigs were (mean +/- SEM): adults (3 months old): less than 1.0 and 22.6 +/- 1.1; euthyroid newborns (0-5 days old): 3.9 +/- 0.4 and 56.5 +/- 11.9; hypothyroid newborns, (0-5 days old): 1.5 +/- 0.3 and 26.5 +/- 9.8. In euthyroid newborns, T4 and T3 levels were significantly higher than in adults (p less than 0.01 for T4 and p less than 0.05 for T3) and in hypothyroid newborns (p less than 0.05). Isometric twitch was recorded from right ventricular papillary muscles by means of a force transducer. Ouabain 10(-6) M increased isometric twitch tension in adults (tension = 0.66 +/- 0.18 g/mm2) by 123.6 +/- 18.2%, in euthyroid newborns (tension = 0.19 +/- 0.04 g/mm2) by 83.6 +/- 14.5%, and in hypothyroid newborns (tension = 0.12 +/- 0.01 g/mm2) by 170.9 +/- 33.8% (p less than 0.01). Ouabain dose-response curve in the range of 10(-7) M-0.5 x 10(-5) M was significantly different (compared by two-way ANOVA) between euthyroid newborns and hypothyroid newborns (p less than 0.01), and between euthyroid newborns and adults (p less than 0.01). Toxic effects of ouabain reflected by the generation of aftercontractions were also age related and were augmented by hypothyroidism in newborns.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone age at birth; method and effect of hypothyroidism.

Bone maturity at birth (or during the neonatal period) can be estimated from the ossified distal femoral epiphyses (FE). In congenital hypothyroidism (CHT) bone maturation is retarded and neonatal bone age reflects the severity of prenatal thyroid failure. In our reference group of 111 healthy infants, the size of these epiphyses depended not only on the age but also on body size. Thus, if bone age is estimated from the size of an epiphysis, the size of the infant is a potential confounder. This problem was avoided by estimating the maturation lag from the difference between the observed and predicted heights of FE (FEHs). Models for predicting FEH were constructed from data from the reference group by multiple linear regression and confirmed in a separate group of 37 healthy infants. In 52 hypothyroid newborns both FEH and FEH lag correlated with serum thyroxine concentration, indicating that FEH can be used as a measure of bone maturation in a population that is fairly homogeneous for (postmenstrual) age and size. Otherwise FEH lag is a better indicator.

Transient primary hypothyroidism in the newborn: Experience of the Victorian Neonatal Thyroid Screening Programme

Between May 1977 and December 1986, the Victorian Thyroid Screening Programme tested approximately 570,000 newborns for congenital hypothyroidism. One hundred and sixty-six cases of primary hypothyroidism, confirmed by formal thyroid function tests, were identified, of which 24 were later found to be transient. In addition, there were two patients with permanent dyshormonogenesis who passed through a stage of being biochemically euthyroid and so could have been diagnosed mistakenly as transient hypothyroidism. Fourteen of the transient cases were due to excessive intake of iodine. In two, this was due to maternal ingestion of iodide during pregnancy and in 12 the babies received large amounts of topical iodine antiseptic. Two cases were caused by maternal anti-thyroid antibodies and in eight instances the cause was unknown. The large number of cases due to the topical application of iodine antiseptic emphasizes the need for caution when using this substance in neonates.

Free triiodothyronine measured in dried blood spots from normal, low-birth-weight, and hypothyroid neonates.

Free triiodothyronine (FT3) has rarely been studied in neonates, primarily because of obvious problems in obtaining serum samples from neonates for research purposes. We adapted an analog radioimmunoassay for measuring FT3 in dried blood samples and used it to assay 361 samples selected from those collected for the screening for neonatal hypothyroidism. The mean FT3 concentration in healthy neonates on the fourth postpartum day is 2.55 pmol per liter of whole blood (SD 0.78 pmol/L, n = 145), the same as in healthy adults. Low-birth-weight infants have a decreased concentration of FT3, and this decrease is much greater in premature neonates than in infants at low weight for gestational age. In six hypothyroid newborns, the FT3 concentration was normal or increased, clearly indicating that FT3 assay is not a diagnostic tool for hypothyroidism. FT3 was barely detectable in one case of congenital galactosemia.

Free thyroxine values in dried blood spots on filter paper in newborns are related to both gestational age and birth body weight.

The results of free thyroxine (FT4) measurements in dried blood spots on filter paper in 744 euthyroid newborns (616 at term, 128 preterm), 10 newborns with congenital hypothyroidism and 4 euthyroid newborns with congenital TBG deficiency are reported. FT4 was measured by column adsorption chromatography of free hormone followed by radioimmunoassay in the eluate. FT4 values averaged 24 +/- 0.2 pmol/L (mean +/- SE) in euthyroid newborns, 23.0 +/- 0.9 pmol/L in euthyroid newborns with TBG deficiency (p = NS), and 5.7 +/- 0.4 pmol/L in hypothyroid newborns (p less than 0.001 vs both groups). Total T4 (TT4) values in newborns with TBG deficiency were not different from those in hypothyroid newborns, but were significantly lower than those in euthyroid newborns without TBG abnormalities. FT4 values were higher in full-term newborns than in preterm newborns (25.2 +/- 0.3 vs 21.2 +/- 0.5 pmol/L, p less than 0.001). In both full-term and preterm newborns FT4 values in dried blood spots increased with birth body weight (bbw), virtually plateauing when bbw was greater than 2,500 g. The cut-off values established on the basis of the bbw (8.0 and 13.1 pmol/L for a bbw of less than or equal to 2,500 g and greater than 2,500 g, respectively) showed higher specificity and predictive value of positive results than the cut-off values based on the gestational age. In any case, the sensitivity, specificity and predictive values of FT4 determinations proved to be higher than those of TT4 and TSH measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatomedin-C/insulin-like growth factor-1 in infants with congenital hypothyroidism during the first week of life.

Levels of somatomedin-C/insulin-like growth factor-1 (Sm-C/IGF-1) were determined in whole blood collected on filter paper from 41 newborns with congenital hypothyroidism and 183 full-term neonates with normal thyroid function. The mean Sm-C/IGF-1 value of the untreated hypothyroid infants (0.10 U/ml) was virtually identical with that of the normal controls (0.11 U/ml). We are unable to confirm earlier findings of others that Sm-C/IGF-1 concentrations are lower in hypothyroid newborns than in normal infants.

Free thyroxin measured in dried blood spots: results for 10 000 euthyroid and 29 hypothyroid newborns.

We measured free thyroxin (FT4) in dried blood samples from 10 000 euthyroid and 29 hypothyroid newborns (three with transient hypothyroidism and 26 permanent). In euthyroids, the mean FT4 concentration was 16.9 (SD 4.5) pmol/L. Preterm babies had low concentrations of FT4, and values were closely related to birth weight when less than 2500 g. Assay of blood-spot FT4 appears to be specific as a test for hypothyroidism screening, yielding 0.42% false positives when a mean minus 2 SD cutoff value (8 pmol/L) was used. Correcting FT4 for birth weight further decreased the false-positive rate, to 0.07%. In all three newborns with transient hypothyroidism, FT4 was less than 8 pmol/L. In 25 of 26 permanent hypothyroids, FT4 ranged from undetectable to 5 pmol/L; in the 26th infant, who had a large ectopic gland, it was 8.2 pmol/L. We believe that FT4 assay offers an attractive improvement over total T4, whether performed as the first screening test or as a confirmatory test in thyrotropin screening programs.