Increased plasma thyroid stimulating hormone in treated congenital hypothyroidism: relation to severity of hypothyroidism, plasma thyroid hormone status, and daily dose of thyroxine.

Plasma thyroid stimulating hormone (TSH) concentrations obtained during the first four years of treatment in 418 children with congenital hypothyroidism, identified by neonatal screening, were examined in relation to paired measurements of plasma thyroxine (n = 1945), free thyroxine (n = 836), triiodothyronine (n = 480), and free triiodothyronine (n = 231), and estimated daily dose of thyroxine at the time of blood sampling. Overall, plasma TSH was above 7 mU/l in 1280 out of 2960 samples (43%); the percentage was not related to severity of hypothyroidism at diagnosis. Mean values for thyroxine and free thyroxine, and to a lesser extent free triiodothyronine, were consistently lower in samples with TSH concentrations over 7 mU/l and this was the case in patients with either severe or less severe hypothyroidism. Raised TSH concentrations were also associated with lower mean doses of thyroxine (micrograms/kg/day) but here the mean doses of thyroxine in children with severe hypothyroidism were higher than in the children with less severe hypothyroidism. The mean dose of thyroxine associated with low/normal TSH values was highest in the first 6 months and fell progressively. Thyroxine dose was significantly related to thyroxine and free thyroxine concentrations but not to triiodothyronine and free triiodothyronine and the latter appeared to be of limited value as measures of plasma thyroid hormone status during treatment.     

Serum thyroxine and thyroid stimulating hormone concentrations after treatment of congenital hypothyroidism.

Serum thyroid stimulating hormone and thyroxine concentrations were monitored in 42 infants who had been treated for congenital hypothyroidism. Serum thyroid stimulating hormone concentrations were raised in 22 of the infants (52%) at 2 to 4 months, in 16 (38%) at 5 to 11 months, in 14 (33%) at 12 to 18 months, and in eight (19%) at 2 to 4 years. Serum thyroxine and the dose of L-thyroxine/kg/body weight were significantly lower in those infants with raised thyroid stimulating hormone concentrations. Thyroid stimulating hormone was appropriately suppressed when the dose of L-thyroxine was increased, and only one child had delayed maturation of the hypothalamic/pituitary/thyroid axis. We believe it is the infant''s rapid gain in weight in the first two years of life that necessitates this decrease in the dose of L-thyroxine/kg body weight and recommend that the treatment of this age group is reviewed every two to three months.     

Persistently raised thyroid stimulating hormone in adequately treated congenital hypothyroidism on long-term follow-up

AIM: To determine the percentage of patients with inappropriate secretion of TSH (ISTSH) in a large cohort of patients with congenital hypothyroidism (CH), and to examine a probable influence of the pretreatment T4 or TSH levels and the etiology of CH on ISTSH by describing the clinical features of these patients. PATIENTS AND METHODS: We retrospectively examined the records, including anthropometric data, clinical findings, and thyroid function tests (TFT), of 500 children diagnosed with CH. Inclusion criteria of ISTSH were appropriate doses of L-T4, improvement of clinical findings, normalization of serum total T4 levels and persistently high TSH concentrations. A group of patients who demonstrated adequate suppression of TSH (<6 mU/l) with therapy among 500 CH patients were chosen randomly as a control group. Both groups were compared with regard to the etiology of CH, and TFT at baseline and during the treatment period. RESULTS: Overall, 27 (5.4%) out of the 500 patients with CH had ISTSH. Nine patients (1.8%) with ISTHS did not show TSH normalization during the follow-up period. Four out of 27 patients with ISTSH had organic lesions (three empty sella, one corpus callosum agenesis) on cranial imaging. No statistically significant difference was found between the groups for etiological classification. The pretreatment T4 and TSH levels in ISTHS and control groups were not significantly different. CONCLUSIONS: Our results suggest that a minority (5.4%) of adequately treated children with CH have persistently raised TSH levels. The delay in normalization of TSH is not related to pretreatment T4 and TSH values or the etiology of CH.     

Factors involved in the rate of fall of thyroid stimulating hormone in treated hypothyroidism

The rate of fall of serum thyroid stimulating hormone (TSH) concentrations in 32 hypothyroid infants (11 boys, 21 girls) was studied after starting treatment with thyroxine to determine whether it was influenced by initial TSH concentration or the cause of the hypothyroidism. Of 27 patients who had isotope scans before treatment was started, 11 (40%) were athyrotic, 10 (38%) had an ectopic gland, and six (22%) probably had dyshormonogenesis. Treatment was started with thyroxine at 100 micrograms/m2/24 hours at a mean age of 26 days (range 14-45). Serum TSH concentrations remained increased in 26 (81%) at 3 months, 20 (62.5%) at 6 months, and nine (28%) at 1 year and beyond. The mean age for serum TSH to reach the normal range was 0.79 years (range 0.15-2.1 years). Diagnosis (in 27 patients) and initial results (in 32) made no difference to the rate of fall.     

Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment

The relationship between the treatment serum thyroxine level and intellectual development at 2 and 6 years was investigated in 46 Norwegian children with congenital hypothyroidism identified by neonatal screening. The level of serum thyroxine during the first 2 years was positively correlated with the Mental Development Index at 2 years of age (Bayley Scales of Infant Development) and the Verbal IQ at 6 years of age (Wechsler Preschool and Primary Scale of Intelligence). Children with a mean serum thyroxine level greater than 180 nmol/L (14 micrograms/dl) during the first year had a significantly higher Mental Development Index at 2 years and Verbal IQ at 6 years than children with serum thyroxine values less than 129 nmol/L (10 micrograms/dl). Boys had a lower Mental Development Index at 2 years of age than girls (86.9 vs 105.1; p less than 0.001) and a higher frequency of elevated serum levels of thyroid-stimulating hormone during the first year (p = 0.001). No signs of toxic effects of a high hormone level at the time of IQ assessment were detected. However, high serum levels of thyroxine at ages 2 to 4 years in girls were related to lower Performance IQ at age 6 years. The results demonstrate that the serum level of thyroxine is of importance in relation to intellectual development. Thyroxine levels above the upper reference range during the first 2 years were related to best intellectual development at 2 and 6 years.     

Thyroid-stimulating hormone, prolactin, and growth hormone response to thyrotropin-releasing hormone in treated children with congenital hypothyroidism

The purpose of the present study was to assess thyroid-stimulating hormone (TSH), prolactin, and growth hormone responses to TRH stimulation in 12 congenitally hypothyroid children adequately treated with L-thyroxine from the first weeks of life. Although clinically euthyroid, six of these children were found to have abnormally high basal serum TSH concentrations despite clinical euthyroidism. Serum triiodothyroxine and L-thyroxine concentrations were normal and did not differ whether the children had elevated or normal basal serum TSH. All six of the children with high basal TSH had an exaggerated TSH response to TRH and 4 of them also had an augmented prolactin response to TRH. The children with normal basal TSH concentrations had normal TSH and prolactin responses to TRH. An abnormal ("paradoxical") elevation of growth hormone concentration in response to TRH was found in four of seven children in a separate group of patients who had prolonged, untreated primary hypothyroidism, but such responses were not found in any of the adequately treated children. These findings suggest the following conclusions: 1) the phenomenon of high serum concentrations of TSH in conjunction with normal L-thyroxine and triiodothyronine levels (and clinical euthyroidism), is prevalent in congenital hypothyroid patients. 2) These patients have an exaggerated response of their pituitary thyrotroph and lactotroph cells to TRH, presumably caused by selective and relative resistance of these cells to the inhibitory effects of thyroid hormones. 3) Congenital hypothyroidism is not associated with abnormal somatotroph cell responses to TRH.     

Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism

OBJECTIVES: To test whether early treatment with a high initial dose of levothyroxine can prevent suboptimal mental development in all neonates with congenital hypothyroidism (CH). STUDY DESIGN: Sixty-one patients, 27 with severe CH and 34 with mild CH, were treated either early (<13 days) or late (> or =13 days) with either a high initial dose of levothyroxine (> or =9.5 microg/kg/d) or a low initial dose (<9.5 microg/kg/d). With these criteria, 4 treatment groups were formed. The results of the Bayley test, performed at the age of 10 to 30 months and expressed as mental developmental index (MDI) and psychomotor developmental index (PDI), were related to socioeconomic status, treatment group, initial free thyroxine (FT(4)) concentration, and mean FT(4) concentration during the first 3 months of treatment (FT(4)-A) and the ensuing 9 months (FT(4)-B). RESULTS: Mean (+/- SD) MDI was 113 +/- 14, and mean PDI was 114 +/- 12. In the severe CH group, only the patients treated early with a high initial dose had normal MDI scores (124 +/- 16), whereas the scores of the other groups ranged from 97 to 103. In contrast, all patients in the mild CH group had normal scores (range, 122-125), except those in the group treated late with a low initial dose, whose score was 110 +/- 10. Forty-three percent of the variance in MDI and PDI scores was explained by treatment factors, such as the treatment group, initial FT(4) concentration, FT(4)-A, and FT(4)-B. CONCLUSIONS: Our data suggest that optimal treatment includes achievement of euthyroidism before the third week of life by initiation of therapy before 13 days with a levothyroxine dose above 9.5 microg/kg/d and maintenance of FT(4) concentrations in the upper normal range during the first year. Thus treated, patients with CH can achieve normal psychomotor development at 10 to 30 months, irrespective of the severity of the disease.     

Congenital hypothyroidism and partial thyroid hormone unresponsiveness of the pituitary in a patient with congenital thyroxine binding albumin elevation

We describe a girl who presented at the age of 6 weeks with cardiogenic shock due to congenital hypothyroidism (serum thyroxine (T4) <12 nmol/l). Thyroxine replacement therapy was instituted. In spite of high total serum T4 levels, thyroid stimulating hormone (TSH) serum values remained elevated. The raised serum T4 levels were the result of congenital elevation of thyroid binding albumin (TBA). Toxic doses of both T4 and triiodothyronine (T3) normalized the elevated TSH levels indicating that the pituitary is responsive to thyroid hormone, albeit at a higher threshold. In patients with congenital TBA elevation and an altered T4 pituitary response requiring thyroid replacement therapy, the measurement of serum free T4 levels is the parameter of choice to monitor treatment.     

Hypothalamo-pituitary hypothyroidism detected by neonatal screening for congenital hypothyroidism using measurement of thyroid-stimulating hormone and thyroxine

The optimal strategy in neonatal screening for congenital hypothyroidism is still a subject of controversy. In Kanagawa Prefecture in Japan, simultaneous thyroid-stimulating hormone (TSH) and T4/fT4 determination has been used, while the results of our program may provide valuable information. Cumulative findings were analysed to determine the type and frequency of thyroid disorders in infants detected by simultaneous TSH and T4/fT4 determination, and the TSH and T4/fT4 screening strategy was validated. A total of 1284130 neonates were screened between October 1979 and September 1997 and infants followed because of low T4/fT4 without elevated TSH (T4 < 51.5 nmol/L or fT4 < 9 pmol/L and TSH < 15 mU/L) were retrospectively analysed. The first survey was carried out within 6 mo of birth and the second in 1998; 258 infants were diagnosed with congenital hypothyroidism at the first medical evaluation, 15 of them with hypothalamo-pituitary hypothyroidism. However, in the second survey, only 8 children were confirmed as having hypothalamo-pituitary hypothyroidism, therefore the incidence detected by the present strategy was 1/160516. Of 8 children with hypothalamo-pituitary hypothyroidism, mental retardation was prevented in 3 owing to early treatment. CONCLUSIONS: Simultaneous measurement of TSH and T4/fT4 is a useful strategy for detecting hypothalamo-pituitary hypothyroidism, but more studies are needed to show the cost-benefits of using this strategy.     

Influence of timing and dose of thyroid hormone replacement on mental, psychomotor, and behavioral development in children with congenital hypothyroidism

OBJECTIVES: To evaluate the influence of initial and postinitial treatment factors on cognitive, psychomotor, and psychological outcome in schoolchildren with congenital hypothyroidism (CH). STUDY DESIGN: We studied 45 patients (19 with severe CH and 26 with mild CH) and 37 control children by correlating initial and postinitial treatment factors (free thyroxine and thyroid-stimulating hormone [TSH] concentrations, and the percentage of overtreatment and undertreatment periods) with the results of neuropsychological tests and behavior (as reported on the Teacher Report Form [TRF]). RESULTS: The global IQ of the children with CH was comparable to that of the controls; visuomotor and verbal scores were lower, and total TRF scores were higher. Ethnic group, previous development, and overtreatment predicted IQ and verbal scores, with higher scores seen for the overtreated patients than for the control children and those patients who had not been overtreated. As initial treatment was less satisfactory, total TRF scores were higher. CONCLUSIONS: Our study suggests that initial and postinitial suboptimal treatment of CH leads to abnormalities in IQ and specific fields. Overtreatment may advance cognitive development in 5-1/2- to 7-year-olds. Suboptimal initial treatment may lead to behavioral problems. We recommend that TSH concentrations be maintained within the normal range in patients with CH.     

Serum thyroxine and thyroid stimulating hormone values in unreferred children with short stature.

Of 449 children aged 6-9 years with heights below the first centile in a total population of 48 221, only 1 had previously undiagnosed hypothyroidism. In a community with well developed health services hypothyroidism is unlikely to be the cause of short stature among primary school children.     

Zinc status and relation to thyroid hormone profile in Iranian schoolchildren

Zinc is an essential element involved in many basic biochemical reactions in thyroid. However, little is known about concentration of this mineral in goitrous Iranian schoolchildren. This study was undertaken to determine the prevalence of zinc deficiency and the current zinc status in goitrous schoolchildren. A cross-sectional study in which 1188 schoolchildren in the age group of 8-13 years were evaluated for goiter prevalence, urinary iodine and zinc status. Zinc measurement was performed by atomic absorption spectrometry apparatus and urinary iodine was measured by digestion method. Goiter was graded according to WHO classification and serum concentration of thyroid hormones and thyroid-stimulating hormone were determined by commercial kits. This study showed an adequate iodine supply. Eleven percent of all cases had low zinc levels and the mean serum zinc concentration was 84.1 +/- 20.7 microg/dl with a significant difference between the boys and girls (86.6 +/- 22.7 microg/dl vs. 82 +/- 18.7 microg/dl, p = 0.017). The mean concentration in goitrous children was 85.1 +/- 23 microg/dl and for those without goiters was 82.6 +/- 16.7 microg/dl which was not statistically significant. No significant difference was noticed between those with low and normal zinc levels in the prevalence of goiter. In view of normal iodine status, other goitrogenic factors should be evaluated to explain the residual goiter prevalence.     

Resetting the detection level of cord blood thyroid stimulating hormone (TSH) for the diagnosis of congenital hypothyroidism

An appraisal of a 17-year primary thyroid stimulating hormone (TSH) screening programme for the detection of congenital hypothyroidism was carried out to establish the reference interval of cord blood TSH in unaffected infants; the mean cord blood TSH concentration of affected infants and the incidence of congenital hypothyroidism in the Najran province of Saudi Arabia. Our findings show a reference interval of cord blood TSH of 2.0-16.8 mU/l in unaffected infants; a mean cord blood TSH concentration of 399 mU/l in affected infants; a false positive rate for the diagnosis of at-risk infants of 1.02% and a congenital hypothyroidism incidence rate of 34/100 000 (1 : 2931) live births. These findings suggest that there is a need to reset the cord blood TSH concentration for the detection of at-risk infants. We suggest that the detection level of cord blood TSH for the recognition of at-risk infants can be set at 90 mU/l rather than the recommended level of 30 mU/l. This should reduce the false positive rate for detection of infants at risk of congenital hypothyroidism.     

Hypercalcemia in infants with congenital hypothyroidism and its relation to vitamin D and thyroid hormones

The circulating concentrations of calcium, phosphorus, and vitamin D metabolites were measured in 25 infants (fifteen to 30 days of age) with congenital hypothyroidism before treatment or during the first 6 months of thyroxine therapy. Five of the children before treatment and four during the early 3 months of treatment had mild hypercalcemia (10.8 to 12.4 mg/dl). Hypercalcemia before treatment did not appear to be related to the vitamin D status of the infant nor to an alteration in vitamin D metabolism, but to the presence of a residual thyroid secretion. In contrast, hypercalcemia during thyroxine therapy was related to vitamin D supplementation, even though the serum calcium concentration could not be correlated with the circulating concentration of any of the vitamin D metabolites assayed and obvious changes in vitamin D metabolism could not be demonstrated.     

Increased urinary excretion of acid mucopolysaccharides and glycopeptides in hypothyroidism following thyroid hormone therapy

Urinary excretion of acid mucopolysaccharides and glycopeptides in the urine of an untreated patient with cretinism were measured before and after thyroid hormone replacement. Urinary uronic acid and hexose excretion in the CPC-precipitated fraction increased four to ten times after thyroid hormone administration. The maximum excretion was observed after 2 months of thyroid replacement. The excreted acid mucopolysaccharides consisted of chondroitin sulphate A/C and minor quantities of heparan sulphate. Urinary excretion of glycopeptides, particularly small molecular glycopeptides rose also four to five-fold with thyroid hormone administration. These data suggest that thyroid hormone markedly influences the metabolism of acid mucopolysaccharides and glycoproteins. Possibly, the lack of thyroid hormone caused a decreased activity of various lysosomal glycosidases and sulphatases.Abbreviations AMPS acid mucopolysaccharide - CPC cetylpyridinium chloride