Evidence of hypothalamic-pituitary thyroid abnormalities in children with end-stage renal disease

Patients with end-stage renal disease may have abnormalities of growth and of gonadal and thyroid hormones, so we attempted to determine the mechanisms that may be involved in the altered thyroid function. We evaluated serum thyroid hormone levels, their changes immediately after hemodialysis, the serum thyrotropin (thyroid-stimulating hormone (TSH) response to thyrotropin releasing hormone, and the circadian pattern of serum TSH in nine children with end-stage renal disease who were between 7 1/2 years and 17 years 1 month of age. Seven patients had been receiving hemodialysis for a median of 3.3 years; the other two were receiving continuous ambulatory peritoneal dialysis. Four patients had low serum total thyroxine (T4) values, and all nine had low free T4 values. Mean concentrations of total T4, free T4, and total triiodothyronine (T3), which were significantly less than normal before hemodialysis, returned to normal levels immediately after dialysis. Postdialysis thyroid hormone increases did not correlate with the decrease in weight or the increase in hematocrit observed immediately after dialysis. All but one patient had basal TSH levels within the normal range. Three patients had a deficient TSH response to thyrotropin releasing hormone, and the TSH response was prolonged in all of them. The mean (+/- SD) nocturnal TSH surge was 50 +/- 68%. Five of the eight patients studied had a nocturnal TSH surge below the normal range (95% confidence limits 47% to 300%). Serum free T4 values correlated with the TSH nocturnal surge (r, 0.73; p less than 0.05). Our findings support the hypothesis that some patients with end-stage renal disease have central hypothyroidism.     

Thyroxine-binding globulin deficiency in early childhood. Postnatal changes in serum concentrations of thyroid hormones and thyroid hormone-binding proteins

Serial determinations of serum thyroxine (T4), triiodothyronine (T3), thyrotropin (TSH), thyroid hormone-binding globulin (TBG), prealbumin (TBPA) and albumin were performed in a euthyroid girl with TBG deficiency and in her mother for a period of 22 months after delivery. At 8 days old the child had a serum TBG concentration around 50% of normal level which remained essentially unchanged during infancy. Total serum T4 and T3 concentrations were low, the free serum T4, free serum T3 and serum TSH concentrations were normal. The mother had received thyroid hormone from the age of 15 years. Her serum TBG level at 6 weeks post partum was similar to that of non-pregnant adults but decreased to about 50% of normal level, indicating a TBG deficiency. She remained euthyroid after withdrawal of T4 therapy. Serum TBPA and albumin concentration were normal in mother and child. An X-linked inheritance of the TBG deficiency was suggested from a study of the family.     

Elevated thyroid-stimulating hormone level in a euthyroid neonate caused by macro thyrotropin-IgG complex

Elevated thyroid-stimulating hormone (TSH) was discovered by routine neonatal screening in a newborn with no clinical symptoms. Thyroid function tests were repeated and confirmed a high TSH value but normal total thyroxine (T4) and triiodothyronine (T3). However, the mother also had elevated serum TSH with normal levels of T4 and T3. The results suggested a transmitted maternal interfering factor, and no treatment was started while further investigation was performed. Gel filtration chromatography of serum from both the infant and the mother showed a peak TSH with molecular mass consistent with a TSH-IgG complex (macro-TSH). TSH in the infant decreased to a normal level within 8 months in accordance with a normal rate of elimination of maternal IgG, whereas the TSH level of the mother remained high. CONCLUSION: This case suggests that interfering macro-TSH should be considered in a euthyroid neonate with elevated serum TSH and normal T4 and T3 levels to avoid unnecessary treatment.     

A case of familial thyroxine binding globulin excess associated with growth hormone deficiency

A 7 years 3 months old Japanese boy with familial thyroxine binding globulin (TBG) excess associated with growth hormone (GH) deficiency is reported. The patients height was 106.4 cm (- 2.86 s.d.) and his bone age was 5 years and 3 months. He had no goiter and his developmental milestones were normal. The serum thyroid stimulating hormone (TSH) was 2.8 μU/mL, triiodothyronine (T₃) 3.1 ng/mL, thyroxine (T₄) 23.4 μg/dL and free T₄ 1.8 ng/dL. The serum TBG level was beyond 80.0 μg/mL, with normal TSH response to the thyrotropin-releasing hormone (TRH) test. Familial study revealed that his grandmother, mother, uncle, younger sister and younger brother had high TBG and T₃ levels, thus an X-linked co-dominant transmission was suggested. The peak GH responses to insulin and clonidine hydrochloride were 5.8 and 8.2 ng/mL, respectively. The mean nocturnal GH concentration was 2.5 ng/mL. His growth velocity increased from 4.8 to 8.4 cm/year and his serum TBG levels decreased gradually after human growth hormone (hGH) treatment.     

McCune-Albright syndrome in a male child: a clinical and endocrinologic enigma.

A 6 5/12-year-old boy with polyostotic fibrous dysplasia, café-au-lait pigmentation of the skin, and precocious pubertal development was studied for two years. Parathormone, calcium, phosphorus, testosterone, cortisol, and growth hormone levels were within normal limits. Urinary 17-ketosteroids, 17-ketogenic steroids, and estrogens were at the upper limits of normal. After GnRH stimulation, there was only a very slight increase in LH and no increase in FSH. There was no increase in TSH after TRH, and plasma levels of T4 and T3 were normal. The plasma prolactin level was within normal limits, and increased after TRH stimulation (with a second, delayed upsurge). Abnormal distribution of 131I in the thyroid was evident, without clearcut evidence of hyperfunctioning areas after TSH stimulation and T3 suppression tests followed by conventional scanning and gamma camera scintiphotography. Our findings do not support the claimed, single, hypothalamic origin of the disease that is presumed to result in overproduction of releasing hormones; they are more in keeping with a pleiotropic, scattered peripheral lesion, possibly of embryonal origin.     

Congenital hypothyroidism in a child with unsuspected familial dysalbuminemic hyperthyroxinemia caused by a mutation (R218H) in the human albumin gene.

We found familial dysalbuminemic hyperthyroxinemia (FDH) in a 5-month-old boy with congenital hypothyroidism (CH) who had a blood thyrotropin (TSH) level of 479 mU/L but normal total serum thyroxine (T4) and higher than normal total triiodothyronine (T3) levels. Thyroid hormone substitution began at 5 weeks of age when T4 and T3 concentrations were below normal. Until the age of 5 months, treatment with levothyroxine was suboptimal on the basis of high serum TSH levels despite above-normal T4 levels. FDH was confirmed by isoelectric focusing and testing of other family members. DNA analysis of the patient revealed R218H, a mutation in the serum albumin gene associated with FDH, which was also present in the patient's euthyroid father and brother. Thyroid scans, serum thyroglobulin measurements, and free T4 measurements using equilibrium dialysis or 2-step immunoassay methods can identify thyroid hormone-binding protein defects and simplify the diagnosis and treatment of infants with CH.     

Thyroid function in thalassaemia major.

Serum concentrations of T4, T3, rT3, and TSH were measured by radioimmunoassay in 45 patients suffering from beta-thalassaemia. A TRH stimulation test was performed and the binding capacity of TBG and TBPA for T3 and T4 measured by reverse flow zone electrophoresis in a group of these patients. Mean T4 serum concentration was lower in thalassaemic patients than controls; T3, rT3, TSH levels, and the pituitary response to TRH were normal. TBPA binding capacity for thyroxine was greatly decreased, probably due to iron overload impairing the liver function. The decreased circulating total thyroxine might be explained by the reduced TBPA capacity, serum free thyroid hormone concentration total thyroxine might be explained by the reduced TBPA capacity, serum free thyroid hormone concentration values being normal. It is concluded that thalassaemic children are euthyroid, despite often having low-normal or subnormal thyroxine levels.     

THYROXINE-BINDING GLOBULIN DEFICIENCY IN EARLY CHILDHOOD

ABSTRACT. Jacobsen, B. B., Hansted, L. C, Brandt, N. J., Haahr, J., Hummer, L., Munkner, T. and Sorensen, S. S. (Department of Paediatrics, Viborg Hospital, Children's Hospital Fuglebakken, Department of Paediatrics, Section of Clinical Genetics and Department of Nuclear Medicine, Rigshospitalet, Copenhagen, Denmark). Thyroxine-binding globulin deficiency in early childhood. Postnatal changes in serum concentrations of thyroid hormones and thyroid hormone-binding proteins. Acta Paediatr Scand, 70:155, 1981. –Serial determinations of serum thyroxine (T4), triiodothyronine (T3), thyrotropin(TSH), thyroid hormone-binding globulin (TBG), prealbumin (TBPA) and albumin were performed in a euthyroid girl with TBG deficiency and in her mother for a period of 22 months after delivery. At 8 days old the child had a serum TBG concentration around 50% of normal level which remained essentially unchanged during infancy. Total serum T4 and T3 concentrations were low, the free serum T4, free serum T3 and serum TSH concentrations were normal. The mother had received thyroid hormone from the age of 15 years. Her serum TBG level at 6 weeks post partum was similar to that of non-pregnant adults but decreased to about 50% of normal level, indicating a TBG deficiency. She remained euthyroid after withdrawal of T4 therapy. Serum TBPA and albumin concentrations were normal in mother and child. An X-linked inheritance of the TBG deficiency was suggested from a study of the family.     

Peripheral insensitivity to thyroid hormones in a euthyroid girl with goitre.

A 9-year-old girl was euthyroid with a small goitre, exophthalmos, scaphocephalic skull, minor sketelal abnormalities, and raised serum thyroid hormone concentrations. Other members of the family did not have goitres and their thyroid hormone levels were normal. From age 3 years the patient was treated for Graves''s disease, but after 4 years treatment was stopped because of enlargement of the goitre. Despite increased serum thyroxine (T4), free T4 (FT4), and triiodothyronine (T3), basal serum TSH, and the TSH response to thyrotropin-releasing hormone (TRH) were normal. Pituitary refractoriness was present because full suppression of the TSH response to TRH was achieved only after daily administration of 500 micrograms thyroxine. Urinary excretion of hydroxyproline, and the activity of red cell glucose-6-phosphate dehydrogenase remained normal when excess T4 was administered, demonstrating the tissue resistance to thyroid hormones. Peripheral lymphocytes were found to have nuclear receptors for T3 with normal affinity, but the relatively low binding capacity indicated that the biochemical defect might be a deficiency of nuclear receptor protein. The findings in this patient differ somewhat from previously reported cases of peripheral resistance to thyroid hormones.     

Congenital hypothyroidism with delayed rise in serum TSH missed on newborn screening

We report on a female patient with congenital hypothyroidism (CH) missed on a newborn screening test. She is now 10 years old with retarded development. The patient was born premature at 34 weeks of gestation with birth-weight of 1515 g, and was judged to be normal in the screening programme of Niigata Prefecture. However, she gradually suffered from poor weight gain and retarded development with stridor at breathing. Serum thyroid stimulating hormone (TSH) levels were rechecked and showed high values with normal T3 and T4 levels. She was referred to our hospital at the age of 13 months. She was diagnosed as having CH (ectopic thyroid) with a delayed rise in blood TSH concentration, probably due to the prematurity of the hypothalamic-pituitary-thyroid axis. l -thyroxine therapy brought a decline in TSH levels with partial improvement of her symptoms. Regardless of the result of newborn screening, infants with elevated serum TSH levels should be carefully examined for possible CH, even when T3, T4 and free T4 values are in the normal range.     

Effects of anticonvulsant drugs on thyroid hormones in epileptic children.

Serum total and free thyroid hormones, reverse T3 (rT3), thyroxin binding globulin (TBG) and thyroid stimulating hormone (TSH) concentrations were measured in 35 epileptic patients receiving anticonvulsants (phenobarbitone, phenytoin). There was a significant reduction found in total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), free triiodothyronine (FT3) and rT3 in the group treated with, phenytoin. The thyroid hormone levels were within normal limits in the group receiving phenobarbitone.     

Serum tri-iodothyronine, thyroxine, and thyrotrophin concentrations in newborns during the first 2 days of life.

The serum concentrations of tri-iodothyronine (T3), thyroxine (T4), and thyrotrophin (TSH) were measured in 10 term newborn infants between birth and the age of 2 days by radioimmunoassay. The mean concentration of T3 in maternal serum was 1.62 mug/l, and it increased from the low cord blood level of 0-63 mug/l to the peak value of 1-76 mug/l within the first 2 hours of life. Mean serum T4 concentrations increased from the cord blood level of 145 mug/l to the peak value of 205 mug/l within the first 24 hours of life. The postnatal increase of the mean serum TSH concentrations from the cord blood level of 5-7 mU/l to the peak value of 20-6 mU/l within 2 hours was similar to the increase of T3. These data confirm earlier reports which show that T3 secretion is low at birth and TSH secretion is stimulated strongly but transiently after birth, and that the low T3 secretion is rapidly normalized in 2 hours along with the TSH release. Because of these strong and rapid changes, we recommend screening of the function of the pituitary-thyroid axis in neonates after the age of 24 hours.     

Anorexia nervosa in male adolescents. II. Psychoneuroendocrinologic findings

Female patients with anorexia nervosa (a.n.) are characterized by distinct endocrine features probably due to hypothalamic pituitary dysfunctions. There is only a limited number of case reports available on patients with a.n.; mostly with few data on hormones. In six male patients with a.n. we examined basal and stimulation values of several hormones performing three pituitary function tests. Basal and stimulated values of luteinizing hormone (LH) and of follicle stimulating hormone (FSH) after LHRH were low comparable to results in prepuberal boys. Similarly, testosterone levels in serum were also markedly reduced. By exploring the pituitary-thyroidal axis total T4 was diminished in one patient and at the lower limit in two patients; concentration of free T4 was in the normal range, while five of six subjects had reduced total T3 concentration and two of six patients showed increased reversed T3 levels; TBG concentration was always in the normal range. Basal TSH was normal, while in two patients the TSH stimulation levels after TRH were diminished; in all patients the TSH stimulation levels were found to be delayed. The basal levels of growth hormone were normal, but the growth hormone response after insulin was diminished in four patients. In all six patients basal prolactin (PRL) and PRL concentration after TRH stimulation was in the normal range. The neuroendocrine results in the six patients with a.n. confirm in males a similar hypothalamic-pituitary dysfunction as it is already known for female patients.     

The use of L-T4 as liquid solution improves the practicability and individualized dosage in newborns and infants with congenital hypothyroidism

Dosage recommendations for the initial therapy of congenital hypothyroidism (CH) in newborns vary between 8 microg/kg/d and 10-15 microg/kg/d. AIM: To evaluate the practicability of LT4 in liquid form and to define the initial dosage for optimal treatment. METHODS: Liquid LT4 solution was administered to 28 consecutive newborns with primary CH. We measured TSH, T3, T4, free T3 and free T4 before therapy and during follow-up up to 2 years. After 2 years a standardized developmental test (Griffith) was performed. RESULTS: The median dosage at start of therapy was 12.3 microg LT4/kg/d and decreased to about 5 microg LT4/kg/d after 9 months. The median time of normalization of TSH (< or =6 mU/l) was 2 weeks. In 21 patients, who received a median starting dosage of 12.7 microg LT4/kg (range 9.8-17.1 microg/kg), TSH levels normalized within a median of 1 week. Seven patients receiving only 10.1 microg LT4/kg normalized their TSH only after a median of 2 months. CONCLUSIONS: Newborns with CH should normalize their TSH within 1-2 weeks. The initial dose necessary to normalize TSH is not lower when a liquid solution is used. The higher dose used in tablets is not due to inefficient absorption, but rather reflects the increased demand for thyroid hormone in the first weeks of life.     

Thyroid function in preterm infants 27-29 weeks of gestational age during the first four months of life: results from a prospective study comprising 80 preterm infants

AIM: Assessment of thyroid function in preterm neonates (PTN) 27-29 weeks of gestational age. PATIENTS AND METHODS: 80 PTN, gestational age 27 weeks in 24, 28 weeks in 28, and 29 weeks in 28. Neonates were classified as healthy (n=17) or sick (n=63). Measurement of serum TSH, free T4, T4, T3 and rT3 in the mother and in the cord at the time of delivery, and in the infant at 1 hour, 24 hours, 1 week, 3 weeks, and 2 and 4 months of postnatal age. RESULTS: In healthy and sick preterms, TSH values peaked at 1 hour and decreased thereafter. Healthy PTN presented a peak in free T4 values at 24 hours that was not observed in sick neonates. Sick PTN had a lower TSH peak and lower free T4 values at 24 hours and 1 week than healthy ones (p < 0.05). Healthy PTN 27-29 weeks had lower TSH peak at 1 hour and lower free T4, T3 and T4 values during the first 2 months than healthy PTN 30-35 weeks (PTN30-35w) previously evaluated (p < 0.05). However, at all postnatal times healthy preterms had free T4 values above -2 SD of the mean values of healthy PTN30-35w. A wide range of free T4 values was observed in the sick group. Free T4 values above -2 SD of the mean values of healthy PTN30-35w were detected in a high proportion of sick PTN (58.3% at 24 hours, 73.5% at 1 week, 93.9% at 3 weeks, 85.1% at 2 months and 100% at 4 months). CONCLUSIONS: Prematurity and disease influence thyroid function, and consequently thyroid function should be individually assessed in preterms 27-29 weeks of gestation during the first 2 months of life.     

Thyroid hormones before and after weight loss in obesity.

BACKGROUND: Little is known about changes in thyroid function in obese children. An influence of leptin on thyroid hormone synthesis has been proposed. AIMS: To examine thyroid function and leptin concentrations in obese children. METHODS: Triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), and leptin were measured in 118 obese children (aged 4.5-16 years); thyroid function was also determined in 107 healthy children of normal weight. T3, T4, and TSH were analysed in 55 obese children who had achieved weight reduction and in 13 obese children who had not achieved weight reduction after one year based on normal energy diet. RESULTS: TSH, T3, and T4 were significantly higher in obese children compared to those of normal weight. Twelve per cent of the obese children had TSH, 15% had T3, and 11% had T4 concentrations above the twofold standard deviation of normal weight children. The degree of overweight correlated with T3, T4, and TSH. Thyroid hormones did not correlate significantly with leptin. A reduction in overweight showed a significant decrease in T3, T4, and leptin serum concentrations, but there was no significant change in TSH. CONCLUSION: Peripheral thyroid hormones (T3, T4) and TSH are moderately increased in obese children; weight reduction leads to a long term decrease in the peripheral thyroid hormones but not in TSH. There is no necessity to treat the increased serum TSH.     

Normal values for circulating thyroid hormones, T3 uptake and thyrotropin before and after TRH. Radioimmunoassay determinations on 182 euthyroid children (author's transl)

Measurements of T4, T3, rT3, T3U, and TSH (before and after TRH stimulation) were performed by RIA. 182 children, apparently euthyroid, age 2/12--14 years, were investigated in a cross sectional study. Free T4RIA and free T3RIA Indices and the ratio rT3/T3 and T4/T3 were calculated. Statistical analysis showed the following results: 1. Geometric mean serum concentrations of T4, T3, rT3 and TSH (basal) show no age related differences; T4 showed a not significant negative slope with age.--2. The ratio rT3/T3 and T4/T3 remains constant.--3. TRH induced TSH release (indicating the activity of the regulatory system) is unchanged from 2/12 to 14 years. Geometric means values, standard deviations and normal ranges are given.     

Effect of long-term GH administration on pituitary-thyroid function in idiopathic hypopituitarism.

Twenty-four euthyroid children with idiopathic pituitary dwarfism were studied. The euthyroid state for seven of these patients was determined by negative physical examinations, normal plasma T4 assays and normal 131I uptakes. For the other children, thyroid function was evaluated with T3 and T4 assays and on the basis of the TRH test. Each of the children was treated with HGH in one of three different ways. The first group (five cases) was given a HGH dose, ranging from 12.4 to 17.2 IU/m2//week. The second and third groups (nine and ten cases, respectively) were treated with 10 and 20 IU/m2/week, respectively. Treatment was carried out for periods ranging from 6 months to 6 years. After no less than 6 months of treatment, and at intervals of 6 months (or some multiple of 6 months) plasma T3 and T4 assays, as well as a TRH test were performed in each patient. In some patients one of the indices was once beyond the upper or lower limit of the normal range (none of the children presented simultaneous abnormal levels of more than one index during the controls). This value, however, returned to within normal limits at the following control. There was no correlation between T3, T4 and TSH with the duration of HGH therapy. There was no significant difference between the groups of children treated with the different HGH doses. These data seem to demonstrate that the risk of inducing an alteration in thyroid function in hypopituitary patients during HGH treatment is very slight, and that the irregularly abnormal thyroid indices observed in some of the children during one of the controls might be an expression of their metabolic status at that moment.     

Raised serum TSH in hypothyroidism.

It is desirable to detect early hypothyroidism of the mildest degree even before conventional tests of thyroid function become abnormal. Serum TSH levels (normal: undetectable to 4 muU/ml) rise in patients with mild hypothyroidism long before serum T4 and T3 levels fall. In the patient described the serum TSH level was 310 muU/ml, while other tests of thyroid function gave normal results. After treatment with thyroxine, serum TSH returned to normal. It should now be accepted that patients with mild hypothyroidism have a raised serum TSH and that thyroid insufficiency can be confidently excluded if the serum TSH concentration is normal. It is thus important to assay serum TSH when suspicion of hypothyroidism is aroused.     

Influence of long-term carbamazepine treatment on thyroid function

We have studied the effects of carbamazepine on thyroid function in sixteen recently diagnosed epileptic children and thirteen epileptic children receiving long-term carbamazepine therapy and compared these findings with the thyroid function of thirteen healthy control subjects. Thyrotropin (TSH), tri-iodothyronine (T₃), thyroxine (T₄), free tri-iodothyorinine (FT₃) and free thyroxine (FT₄) serum levels were determined in both recently diagnosed but as yet untreated epileptic children and normal controls. These hormone levels were determined again after 2 months of treatment and 12 months of treatment in epileptic children. No statistically significant difference was found in the endocrine parameters of untreated epileptic children and the normal control group. After both 2 months and 12 months of carbamazepine therapy, serum levels of T₄, FT₄ and FT₃ were found to be low, but the serum T₃ concentration was unaffected. Baseline TSH levels were not changed during carbamazepine therapy either. Serum TSH levels increased rapidly after thyrotropin-releasing hormone stimulation in both the before and 12 months after carbamazepine treatment groups, but the response was higher in the 12 months treatment group. The findings of the present study suggest that accelerated hormone metabolism is responsible for hormonal changes found in patients treated with carbamazepine. Carbamazepine also had effects on the function of the hypothalamo-pituitary axis.