Successful therapy with L-T4 in a 5 year-old boy with generalized thyroid hormone resistance

Resistance to thyroid hormone (RTH) is a rare dominantly inherited disorder caused by mutations in the thyroid hormone receptor beta gene which lead to impaired tissue responsiveness to thyroid hormone (TH). RTH is characterized by elevated free thyroid hormone and unsuppressed thyrotropin (TSH) levels. Two types of the disorder have been recognized: selective pituitary resistance and generalized resistance to TH (GRTH). Triiodothyroacetic acid has been used in patients showing hypermetabolism, and L-T4 treatment in high doses has been suggested in GRTH if patients have signs of clinical hypothyroidism such as growth retardation and developmental delay. The outcome of long-term treatment of GRTH with L-T4 has not yet been reported. We report a 5 year-old boy who presented with severe growth retardation, fatigue and speech delay. He had hyperactivity despite feeling tired easily. Elevated TH levels with unsuppressed TSH and delayed bone age were determined by laboratory evaluation and he was diagnosed as GRTH. There was no clinicical evidence of hypermetabolism. We could not demonstrate any mutation in thyroid receptor beta1, beta2 or alpha gene of this patient and his parents. L-T4 treatment was started at conventional doses (6 microg/kg), and after 3 months of treatment T4 and TSH levels were suppressed successfully. In 12 months of treatment, no side effects were detected and surprisingly clinical symptoms improved without requirement for high doses of L-T4.     

Thyroid Hormone Resistance in children

Thyroid Hormone Resistance (RTH) is characterized by the diminished response of thyroid hormone-responsive tissues in varying degrees in association with elevated serum levels of total and free T4 and T3 and inappropriately normal or elevated TSH levels. In almost all cases it is due to different mutations in only one allele of the thyroid hormone receptor beta gene which blocks the action of normal allele thus producing dominantly inherited RTH. In RTH, varying degrees of target tissue responsiveness result in a heterogenous clinical presentation. Resistance in the thyrotrophs and the peripheral tissues is assessed by the evaluation of TSH secretion and changes in peripheral markers of thyroid hormone action after administration of L-T3, respectively. The treatment decision depends on the individual characteristics of each patient. Patients with hypothyroid and hyperthyroid symptoms may require treatment with thyroid hormone and with agents such as beta blockers, antithyroid drugs and thyroid hormone analogues.     

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.     

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.     

Relationship between serum leptin and thyroid hormones in children

BACKGROUND: Because leptin decreases food intake and increases energy expenditure, the possible influence of thyroid status on the leptin system has been investigated mainly in adults and animals. However, the data available at present are very confusing. The aim of the present study was to assess the possible interaction of thyroid hormones with the leptin system. METHODS: Serum free thyroxine (FT4), a biologically active thyroid hormone, and thyroid stimulating hormone (TSH), a sensitive and reliable index of thyroid status, were examined in 51 children (19 males, 32 females) with mass screening-detected congenital hypothyroidism on continuous L-thyroxine (L-T4) substitution therapy. The subjects were divided into younger (n = 35, aged 1 month-5 years) and older (n = 16, 6 years-11 years) children groups. Serum levels of leptin and thyroid hormones were measured in the subjects. Body mass index (BMI) was estimated by the formula bodyweight (kg)/height x height (m2), which is known as the Kaup index in younger children and BMI in older children and adults. RESULTS: In the younger children group, serum leptin levels showed no correlation with serum TSH, FT4 or T4. In the older children group, serum leptin concentrations significantly correlated with T4 (r = 0.510, P < 0.05) and BMI (n = 16, r = 0.647, P < 0.01), but not with TSH or FT4. CONCLUSION: The role of thyroid hormones in modulating leptin synthesis and secretion seems to have little, if any, clinical or biological relevance.     

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.     

Serum concentrations of thyrotropin, thyroid hormones and thyroid hormone-binding proteins during acute and recovery stages of idiopathic respiratory distress syndrome.

A total number of 27 premature infants with idiopathic respiratory distress syndrome (IRDS) and 52 healthy controls with comparable gestational age and body weights were studied during the first month of life. In infants with IRDS a reduced thyrotropin (TSH) response to birth was suggested, as serum TSH was lower in IRDS patients than in controls during the first two days of life. Low serum concentrations of thyroid hormones were found in the acute stage of IRDS reaching minimal values by day 3--5. After that period an increase in thyroid hormone levels occurred. The serum T2 increased to the level of healthy prematures by day 6--10, whereas the serum T4 increased to normal levels by day 21--30. Serum concentrations of thyroxine-binding globulin (TBG) were significantly lower in IRDS patients than in healthy controls; a gradual increase to normal levels occurred during recovery. Serum prealbumin (TBPA) levels in IRDS infants increased rapidly after birth and exceeded levels of healthy infants. Serum albumin values were not significantly different in the two groups of infants. The serum T4/TBG ratios were low during recovery from IRDS.     

Hyperthyroxinämie mit kardialer Symptomatik

Resistance to thyroid hormone (RTH) is a rare autosomal dominant inherited disease, which is usually caused by mutations in the TRβ-gene. The clinical presentation of RTH is highly variable and patients can show signs of euthyroidism, hypothyroidism and/or hyperthyroidism. We report on a 12¹¹/₁₂ year old girl who was admitted to hospital with tachycardia. Laboratory tests showed high levels of serum free T3 and free T4 in the presence of non-suppressed TSH concentrations. Further investigations, including molecular genetic tests, were then performed and revealed a rare case of thyroid hormone resistance. Our case report demonstrates that patients with RTH may manifest only cardiovascular symptoms.     

Serum free T4 and thyroid stimulating hormone levels in preterm infants and relationship between these levels and respiratory distress syndrome

BACKGROUND: There have been few studies of the thyroid stimulating hormone (TSH) surge in extremely low-birthweight (ELBW) infants, and the relationship between thyroid hormones and respiratory distress syndrome (RDS) has yet to be clarified. The present study sought to determine the serum levels of free T4 (fT4) and TSH in ELBW infants and to examine the relationship between these levels and the development of RDS. METHODS: The authors measured serum fT4 and TSH levels soon after birth in 449 preterm infants, who were born at 22-36 weeks of gestation, and determined the associations between these levels, the incidence of RDS, and the recognized clinical factors associated with RDS. RESULTS: Serum fT4 and TSH levels, and the fT4/TSH ratio, in the group at 22-24 weeks of gestation were significantly lower than those in the group at 28-36 weeks. The levels and ratio increased significantly with increasing gestational age. There were significant correlations between the serum fT4 level and the birthweight, Apgar score, and gender, and between the serum TSH level and the gestational age, mode of delivery, and birthweight. No significant relationship between the incidence of RDS and the serum levels of fT4 and TSH was observed. CONCLUSION: The authors' results suggest that the serum levels of fT4 and TSH in ELBW infants are very low, and that these levels are not correlated with the occurrence of RDS.     

Prolactin and thyrotrophin response to thyrotrophin-releasing hormone in growth hormone deficiency.

Basal and thyroid-releasing hormone-stimulated (200 micrograms/m2) prolactin and thyroid-stimulating hormone (TSH) levels were measured in 31 patients with hypopituitarism (13 isolated growth-hormone deficiencies and 18 multiple pituitary hormone deficiencies). The results were compared with the prolactin response in 76 healthy prepubertal children. Normal prolactin concentrations were found in 13 patients whereas 11 had increased levels. TSH levels were either normal or increased in patients who were considered to have hypothalamic disorders. Decreased prolactin response was present in 7 children, 6 of whom had multiple pituitary deficiencies. Their TSH response was decreased as well, indicating pituitary failure. There was good overall correlation of peak prolactin with peak, TSH concentrations. Some patients with ''isolated'' growth hormone deficiency had an abnormal prolactin response indicating an additional hormonal deficiency. All patients with low levels of serum thyroxine had abnormal prolactin or TSH levels, high in some, low in others. Two euthyroid patients with increased prolactin stimulation became hypothyroid during treatment with growth hormones, thus questioning whether prolactin is a more sensitive indicator of early thyroid insufficiency than thyroxine or TSH levels.     

Effect of perinatal asphyxia on thyroid-stimulating hormone and thyroid hormone levels

AIM: To compare serum concentrations of thyroid hormones--T4, T3, free T4 (FT4) and reverse T3 (rT3)--and thyroid-stimulating hormone (TSH) found in the umbilical cord blood of term newborns with and without asphyxia and those found in their arterial blood collected between 18 and 24 h after birth. A further aim of the study was to assess the association between severity of hypoxic-ischemic encephalopathy and altered thyroid hormone and TSH levels, and between mortality and FT4 levels in the arterial blood of newborns between 18 and 24 h of life. METHODS: A case-control study was carried out. The case group comprised 17 term newborns (Apgar score < or = 3 and < or = 5 at the first and fifth minutes; umbilical cord blood pH < or = 7.15) who required bag and mask ventilation for at least one minute immediately after birth. The control group consisted of 17 normal, term newborns (Apgar score > or = 8 and > or = 9 at the first and fifth minutes; umbilical cord blood pH > or = 7.2). Cord blood and arterial blood samples were collected immediately after birth and 18 to 24 h after birth, respectively, and were used in the blood gas analysis and to determine serum concentrations of T4, T3, FT4, rT3 and TSH by radioimmunoassay. All newborns were followed-up until hospital discharge or death. RESULTS: Gestational age, birthweight, sex, size for gestational age, mode of delivery and skin color (white and non-white) were similar for both groups. No differences were found in mean levels of cord blood TSH, T4, T3 and FT4 between the groups. In the samples collected 18 to 24 h after birth, mean levels of TSH, T4, T3 and FT4 were significantly lower in the asphyxiated group than in the control group. Mean concentrations of arterial TSH, T4 and T3 between 18 and 24 h of life were lower than concentrations found in the cord blood analysis in asphyxiated newborns, but not in controls. In addition, asphyxiated newborns with moderate/severe hypoxic-ischemic encephalopathy presented significantly lower mean levels of TSH, T4, T3 and FT4 than those of controls. None of the asphyxiated newborns with FT4 > or = 2.0 ng/dl died; 6 out of the 11 asphyxiated newborns with FT4 < 2.0 ng/dl died. CONCLUSIONS: Serum concentrations of TSH, T4, T3 and FT4 are lower in asphyxiated newborns than in normal newborns between 18 and 24 h of life; this suggests central hypothyroidism secondary to asphyxia. Asphyxiated newborns with moderate/severe hypoxic-ischemic encephalopathy present a greater involvement of the thyroid function and consequently a greater risk of death.     

Thyroid hormone profile in children with goiter in an endemic goiter area

The thyroid hormone profile was investigated in goitrous schoolchildren aged 6-11 years living in Antalya, an area with mild/ moderate iodine deficiency. With few exceptions, the serum levels of T4 and TSH were in the normal range in children with different grades of goiter. Compensatory elevated T3 levels were detected in 24% of the subjects. Thyroid hormones did not differ significantly with respect to the urinary iodine (UI) level. No correlations were found between thyroid volume, UI excretion level and thyroid hormones. It was concluded that thyroid hormones, except compensatory T3 elevation in some subjects, were not affected significantly in a mild/moderate iodine deficient area.     

The thyroid hormone system in mucoviscidosis

Endocrine disorders do not represent primary manifestations in children with cystic fibrosis. Abnormal thyroid gland function is commonly observed in patients with chronic nonthyroidal illnesses. Serum concentrations of TSH, T4 and T3 were measured and a TRH-stimulation test (200 micrograms Relefact per kg body weight) was performed in 24 patients with CF 6 to 16 1/2 years of age. As compared to the controls, CF patients had increased basal TSH and lower T4 and T3 concentrations. Finally they exhibited higher TRH-stimulated TSH and decreased peripheral T4 and T3. There was no correlation to the nutritional status or the Shwachman scores. In all patients with CF albumin, TBG and TBPA were also normal. Our results indicate a subclinical hypothyroidism in CF. Routine therapy with thyroid hormones is neither necessary nor recommended.     

Hyperthyrotropinemia in a neonate with normal thyroid hormone levels: the earliest diagnostic clue for pseudohypoparathyroidism

A neonatal case of hyperthyrotropinemia is described in association with pseudohypoparathyroidism (PHP). This girl was found to have high serum thyrotropin (TSH) on screening, though serum thyroid hormones were within the normal ranges throughout the observation. The patient's TSH remained above the normal limit until 5 years of age, when she suffered from hypocalcemic tetany and was diagnosed as type-1 PHP on the basis of responsiveness to parathyroid hormone. She also had stigmata of Albright's hereditary osteodystrophy. The results demonstrate that elevated TSH, although thyroid hormone concentrations are normal and medication is not indicated, may be one of the earliest diagnostic clues for PHP.     

Plasma thyroid hormones and prolactin in premature infants and their mothers after prenatal treatment with thyrotropin-releasing hormone.

We assayed TSH, triiodothyronine, free thyroxine, and prolactin (PRL) in plasma of women and infants participating in a trial of prenatal thyrotropin-releasing hormone (TRH) treatment for prevention of newborn lung disease. Women in labor at 26-34 wk of gestation received 400 micrograms of TRH i.v. every 8 h (one to four doses) plus 12 mg betamethasone (one or two doses); controls received saline plus betamethasone. Mean cord concentrations in control infants were TSH 9.7 mU/L, triiodothyronine 0.6 nmol/L (40.2 ng/dL), free thyroxine 14.4 pmol/L (1.13 ng/dL), and PRL 67.6 micrograms/L. TRH increased maternal plasma TSH by 100% at 2-4 h after treatment and decreased levels by 28-34% at 5-36 h. In cord blood of treated infants delivered at 2-6 h, TSH, triiodothyronine, and PRL were all increased about 2-fold versus control, and free thyroxine was increased 19%; the response was similar after one, two, three, or four doses of TRH. In treated infants delivered at 13-36 h, cord TSH and triiodothyronine levels were decreased 62 and 54%, respectively, and all thyroid hormones were lower after birth at 2 h of age versus control. We conclude that prenatal TRH administration increases thyroid hormones and PRL in preterm fetuses to levels similar to those normally occurring at term. Pituitary-thyroid function is transiently suppressed after treatment to a greater extent in fetus than mother, and infants born during the early phase of suppression do not have the normal postnatal surge in thyroid hormones.     

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.     

Thyroid hormone abnormalities at diagnosis of insulin-dependent diabetes mellitus in children

Comprehensive evaluation of thyroid hormone indices was performed in 58 children with insulin-dependent diabetes mellitus (IDDM) at the time of diagnosis and prior to insulin therapy. Two patients were found to have primary hypothyroidism, with markedly elevated TSH and very low T4, free T4, T3, and reverse T3 concentrations. The remaining 56 patients had the transient alterations in thyroid hormone indices that are characteristic of "euthyroid sick" or "low T3" syndrome. Mean TSH and reverse T3 values were significantly higher and the mean T3, T4, and free T4 levels were significantly lower than those observed in the control population. Ten of the diabetic patients had elevated TSH concentrations and normal or low free T4 values; eight had normal TSH levels and low T4 and free T4 values. The remainder of the group had thyroid indices compatible with abnormal peripheral metabolism of thyroid hormones. Elevated titers of antimicrosomal antibodies were found in 16% of the children with IDDM. We conclude that abnormal peripheral metabolism and altered hypothalamic-pituitary function are responsible for the transient changes in thyroid hormone indices in patients with untreated IDDM. The most reliable indicators of concomitant primary hypothyroidism in untreated IDDM are markedly elevated TSH and low reverse T3 values.     

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.     

苯巴比妥、苯妥英、卡马西平对癫痫患儿甲状腺激素的影响

观察常用抗癫痫药物对癫痫患儿血清甲状腺激素的影响。对无甲状腺功能减退临床表现的癫痫患儿(各组均20例)共80例,应用RIA法测定血清TT4、TT3、FT4、FT3、rT3、TSH浓度。结果未经治疗癫痫患儿所有激素水平与正常对照组比较无显著差异,苯巴比妥组FT4值低于正常对照组(P<0.01),卡马西平组TT4、FT4值也明显降低(P<0.01),苯妥英组TT4、FT4、FT3值均显著降低(P<0.01),所有各组rT3、TSH无改变。资料表明,抗癫痫药物对甲状腺激素影响强度依次为苯妥英钠、卡马西平、苯巴比妥。     

Familial partial peripheral and pituitary resistance to thyroid hormone: a frequently missed diagnosis?

The diagnosis of partial peripheral and pituitary resistance to thyroid hormone was ultimately made in two boys, 7 and 9 years of age, and a 10-year-old girl who had goiters and hyperthyroxinemia. The boys were treated with propythiouracil and/or thyroidectomy or iodine 131 for suspected thyrotoxicosis but had poorly suppressible serum thyroid-stimulating hormone (TSH) post treatment in spite of the usual L-thyroxine replacement. The girl had increasing goiter size while receiving propylthiouracil, 100 mg every eight hours. These findings led to reevaluation of thyroid hormone dynamics in these children and their families. Twelve additional family members, 3 to 38 years of age, compatible with an autosomal dominant inheritance, were also found to have peripheral and pituitary resistance to thyroid hormone. All affected individuals had elevated serum thyroxine and triiodothyronine levels, normal to slightly elevated triiodothyronine resin uptakes, and a nonsuppressed serum TSH. The five individuals who were given thyrotropin-releasing hormone showed exaggerated TSH responses, which normalized on L-thyroxine therapy. Misdiagnosis in six of 15 family members led to significant morbidity (hypothyroidism, delayed growth, and therapy risk). A nonsuppressed serum TSH in a patient with suspected thyrotoxicosis should lead to suspicion of this disorder. Appropriate management for this condition includes L-thyroxine therapy to decrease goiter size and normalize TSH responses to thyrotropin-releasing hormone.