OBJECTIVE: Changes in the functional state of beta cells by neonatal stimulation or adolescent suppression have reduced the incidence of type 1 diabetes mellitus in animal models. The aim of this study was to evaluate the effect of manipulation of the activity of the thyroid gland by neonatal stimulation or by adolescent suppression on the prevalence of spontaneous autoimmune thyroiditis (AIT) in rats. METHODS: Bio-Breeding/Worcester (BB) rats were treated neonatally with sodium iodine (NaI) or thyroid stimulating hormone (TSH), or during adolescence by triiodothyronine (T(3)), and the lymphocytic infiltration in the thyroid gland was evaluated. RESULTS: Neonatal treatment with NaI decreased the prevalence of AIT to 32+/-9% compared with 66+/-5% in the controls (P<0.002), mainly caused by a reduction among the female rats (13+/-9% vs 52+/-8%, P<0.006). TSH had no effect. Post neonatal suppression of the thyroid gland by T(3) had a biphasic response. Early in adolescence the overall prevalence was 14+/-7% compared with 66+/-5% in the controls (P<10(-5)); for female rats AIT was prevented (0+/-0%) compared with 52+/-8% in the controls (P<0.0003) and in male rats the values were 29+/-13% compared with 80+/-6% in the controls (P<0.001). Treatment with T(3) later in adolescence increased the overall prevalence to 81+/-7% compared with 66+/-5% in the controls (not significant). For female rats the prevalence increased to 78+/-9% compared with 52+/-8% in the controls (P=0.04). The degree of thyroiditis among the affected animals was similar in all groups. CONCLUSION: Neonatal stimulation of the thyroid gland by iodine or early adolescent suppression by T(3) reduced the prevalence of AIT whereas T(3) given later increased the prevalence of thyroiditis in rats. Thyroid activity at various ages seems to be of importance for the development of autoimmune thyroiditis.
ML Hartoft-Nielsen, AK Rasmussen, A Kaas, U Feldt-Rasmussen, and K Buschard
M Salerno, T Lettiero, A Esposito-Del Puente, V Esposito, D Capalbo, A Carpinelli, S Padula, and A Del Puente
OBJECTIVE: To evaluate whether long-term l-thyroxine therapy in young adults with congenital hypothyroidism may affect bone mineral density (BMD). DESIGN: Thirty-seven subjects with congenital hypothyroidism, detected by neonatal screening and longitudinally followed from the time of diagnosis and treatment (26+/-4 days) up to the age of 17.8+/-1.0 years, were studied. METHODS: Spinal (L2-L4) BMD, measured by dual-energy X-ray densitometry, and bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) by quantitative ultrasound, were evaluated. RESULTS: Z-score mean values (+/-s.d.) of BMD (-0.3+/-0.7) and Ad-SoS (-0.7+/-1. 1) were slightly below the average but within the normal range. Ad-SoS resulted in a z-score below -1 in 38% of patients as compared with BMD which resulted in a z-score below -1 in only 13.5% of subject. No significant differences were observed between males (BMD, -0.3+/-0.7; Ad-SoS, -0.9+/-1.0) and females (BMD, -0.3+/-0.7; Ad-SoS, -0.5+/-1.2) or when dividing patients on the basis of aetiological defects; ectopic gland (BMD, -0.3+/-0.6; Ad-SoS, -0.8+/-0.9), athyreosis (BMD, -0.3+/-0.9; Ad-SoS, -0.8+/-1.0) and eutopic gland (BMD, -0.3+/-0.8; Ad-SoS, -0.4+/-1.3). No significant relationships were observed between BMD or Ad-SoS z-score and hormonal status or l-thyroxine dosages at the time of the study or during the pubertal period. CONCLUSIONS: The careful monitoring of serum thyroid-stimulating hormone and adjustment of l-thyroxine dosage avoided the significant deleterious effects of prolonged l-thyroxine replacement therapy on bone tissue in adolescents and young adults with congenital hypothyroidism treated from the neonatal period.
M Peter, K Bunger, SL Drop, and WG Sippell
We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2). presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.
Michel Polak, Jo Blair, Primoz Kotnik, Effie Pournara, Birgitte Tønnes Pedersen, and Tilman R Rohrer
To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD).
NordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting.
Patients (n = 172) treated to NAH (height at ≥18 years, or height velocity <2 cm/year at ≥16 (boys) or ≥15 (girls) years) were grouped by age (years) at treatment start (early (girls, <8; boys, <9), intermediate (girls, 8–10; boys, 9–11) or late (girls, >10; boys, >11)) and GHD severity (<3 ng/mL or 3 to ≤10 ng/mL). Multiple regression analysis was used to evaluate the effect of age at treatment start (as a categorical and continuous variable) on NAH standard deviation score (SDS).
Age at treatment start had a marked effect on NAH SDS; NAH SDS achieved by patients starting treatment early (n = 40 (boys, 70.0%); least squares mean (standard error) −0.76 (0.14)) exceeded that achieved by those starting later (intermediate, n = 42 (boys, 57.1%); −1.14 (0.15); late, n = 90 (boys, 68.9%); −1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start.
Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.
Mirjana Barjaktarovic, Tim I M Korevaar, Romy Gaillard, Yolanda B de Rijke, Theo J Visser, Vincent W V Jaddoe, and Robin P Peeters
The cardiovascular system is a known target for thyroid hormone. Early-life cardiovascular alterations may lead to a higher risk of cardiovascular disease in adulthood. Little is known about the effects of thyroid hormone on cardiovascular function during childhood, including the role of body composition in this association.
Population-based prospective cohort of children (n = 4251, median age 6 years, 95% range: 5.7–8.0 years).
Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured to assess thyroid function. Left ventricular (LV) mass was assessed with echocardiography. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (CFPWV). Systolic and diastolic blood pressure (BP) was measured. Body composition was assessed by dual-energy X-ray absorptiometry scan.
FT4 was inversely associated with LV mass (P = 0.002), and with lean body mass (P < 0.0001). The association of FT4 with LV mass was partially mediated through variability in lean body mass (55% mediated effect). TSH was inversely associated with LV mass (P = 0.010), predominantly in boys. TSH was positively associated with systolic and diastolic BP (both P < 0.001). FT4 was positively associated with CFPWV and diastolic BP (P < 0.0001, P = 0.008, respectively), and the latter association attenuated after adjustment for CFPWV.
At the age of 6 years, higher FT4 is associated with lower LV mass (partially through effects on lean body mass) and with higher arterial stiffness, which may lead to higher BP. Our data also suggest different mechanisms via which TSH and FT4 are associated with cardiovascular function during early childhood.
Stanley M. Lee, Elmer Lightner, Marlys Witte, Sharon Oberfield, Lenore Levine, and Maria I. New
A 9 year old Mexican boy presented with severe hypertension, hypokalaemia and features suggesting acute glomerulonephritis. Nephrosclerosis was present on renal biopsy. Aldosterone levels were unresponsive to variations in dietary salt intake and plasma renin activity was suppressed. Following oral dexamethasone therapy (2 mg/day), plasma aldosterone decreased to undetectable levels, serum potassium normalized and plasma renin activity gradually increased. Dexamethasone also restored the normal responsiveness of the renin-aldosterone system to postural stimuli.
The patient exhibited a marked response to a single dose of ACTH with a rise in plasma aldosterone. Long-term blood pressure control and normal potassium levels have been achieved with oral prednisone therapy (5 mg/day) for a period of one year. This case of dexamethasone suppressible hyperaldosteronism (DSH) illustrates that the degree of hypertension in this syndrome may produce severe renal microvascular lesions. DSH should be considered in all children who present with low renin hypertension.
Kerstin Hall, Gösta Enberg, Martin Ritzén, Håkan Svan, Linda Fryklund, and Kazue Takano
Serum somatomedin A (SMA) has been determined in healthy children (n = 188) in relation to age using both a radioimmunoassay and a radioreceptor assay. The SMA levels, only 50% of adult values at birth, rise gradually with age and reach adult levels at 10 years of age. There is a significant correlation (r = 0.46, P < 0.001) between SMA determined by the two methods throughout childhood except during puberty. Immunoreactive SMA shows a marked pubertal rise in values with a peak 2 years earlier for girls than boys, which is not observed by the radioreceptor assay technique. In boys with delayed puberty the increase in immunoreactive SMA is seen first when the testes reach a size of 5 ml. Children with growth hormone deficiency (n = 30) had significantly lower levels of SMA than healthy age-matched controls. Immunoreactive SMA gives a better separation of these groups than the values obtained by radioreceptor assay.
Bjarne Lund, Niels Clausen, Birger Lund, Else Andersen, and Ole H. Sørensen
Circulating 1,25-dihydroxyvitamin D (1,25-(OH)2D) was measured in 87 children aged 3 months to 15 years, and in 11 adolescents 16–19 years of age. A positive correlation to growth velocity was observed, indicating that the biologically active vitamin D metabolite is an important physiological factor in the regulation of growth and development of the skeleton.
A. Parra, S. Villalpando, E. Junco, B. Urquieta, S. Alatorre, and G. García-Bulnes
Serum thyrotrophin (TSH), thyroxine (T4), triiodothyronine (T3), thyroxine-binding globulin (TBG) and reverse T3 (rT3) were measured by radioimmunoassay in 175 girls and 187 boys aged 6.0 to 16.9 years, who were clinically healthy, and had negative serum antithyroglobulin and antimicrosomal antibodies. All the children had normal weight and height and were grouped at 12 months' intervals. In girls, TSH levels ranged between 5.3 ± 0.4 and 6.9 ± 0.5 μU/ml without significant changes with age; serum T4 decreased up to 13.9 years and rose afterwards; serum TBG was constant up to 13.9 years, decreased subsequently and rose after 15.9 years; serum T3 levels were lower after 13.0 years than previously; serum rT3 decreased between 11.0 and 11.9 years and rose thereafter; the calculated serum free T4 (FT4) and free T3 (FT3) concentrations had a significant rise from 14.0 to 15.9 years followed by a sharp decline; T3:T4, rT3:T3 and rT3:T4 ratios were constant up to 11.9 years, then a rise was seen in T3:T4 and a fall in the later ratios, followed by a drop in T3:T4 ratio and a sustained rise in rT3:T3 and rT3:T4 ratios. In boys, TSH levels were constant between 5.2 ± 0.4 and 6.6 ± 0.4 μU/ml; serum T4 decreased with increasing age; serum TBG was constant up to 13.9 years, and had a sustained fall thereafter; serum T3 was constant over the age range studied; serum rT3 levels decreased up to 13.9 years and rose thereafter; FT4 had no changes with increasing age while FT3, although constant up to 13.9 years, had a sustained rise afterwards; T3:T4 ratio did not change with age, while rT3:T3 and rT3:T4 ratios, although constant up to 13.9 years, showed a tendency toward a sustained rise thereafter. These sex-different variations in serum thyroid hormone concentrations might be related to the fact that girls mature at an earlier chronological age than boys and may represent a partial response of the body to the qualitatively and quantitatively different energy needs in girls as compared with boys, consecutive to the differences in body composition first appearing at puberty.
Seppo Leisti and Jaakko Perheentupa
An im vasopressin test was given to 141 children and adolescents, 52 with normal HPA axis and 89 with evident or suspected defect of the axis, and repeated in 36 cases, to establish criteria of a normal response, and to examine the accuracy and precision of the responses. Comparisons were made with the responses to the 2-h ACTH, insulin and 3-h metyrapone test.
The distributions of plasma cortisol levels and increments were positively skew, and a log transformation was made for appropriate statistical analysis. Maximal plasma cortisol level was positively and maximal increment negatively correlated with the basal level. In precision, the maximal level was superior to the maximal increment. Hence, a normal result was best defined by an area around the regression of maximal level on basal level in the normal series. The best single index of the response was the maximal level. A useful new method was introduced for quantitative comparison of plasma cortisol responses to different tests.
The vasopressin test result was frequently normal in patients who, according to repeated insulin tests were ACTH-deficient. Furthermore, the 10 patients with organic expansive hypothalamic lesions had a mean vasopressin response, that was greater relative to the insulin response than that of the reference series. However, 3 of 21 patients with organic non-expansive hypothalamic disease gave a subnormal vasopressin response but a normal insulin response. Moreover, in isolated GH deficiency and after prednisone medication the mean vasopressin response was lower relative to the insulin response than in the reference series. Thus, this test is not reliable in screening for, or in anatomical diagnoses of ACTH deficiency.