M. F. Siracusano

Changes in thyroid function tests induced by 2 month carbamazepine treatment in l-thyroxine-substituted hypothyroid children

In five l-thyroxine-substituted hypothyroid children with partial epilepsy serum total thyroxine (T4) and free T4 (FT4) significantly (P<0.01) decreased following 2 months of carbamazepine (CBZ) administration (20 mg/kg per BW per day) from mean (±SD) values of 12.7±1.1 μg/dl and 15.5±1.8 pg/ml to mean values of 7.5±2.3 and 10.1±1.7, respectively. In all but one patient important changes in both serum total and free triiodothyronine (T3, FT3) were not observed; consequently T3∶T4 and FT3∶FT4 ratios significantly (P<0.05) increased in the whole series. Three subjects had post-treatment serum TSH that rose to hypothyroid levels parallel to a T4 decrease. The negligible thyroid hormone secretion and the unmodified T3-uptake (T3U) or T4-binding globulin (TBG) exclude direct effects of CBZ on thyroid gland and on carrier serum proteins, respectively. The findings observed, instead, might be due to accelerated T4 metabolic clearance together with augmented T4 to T3 conversion rate, as previously demonstrated for diphenylydantoin. The sharp reduction in T4 and FT3 concentrations is the peripheral display of this event, which is associated with a decompensation of the metabolic status, as indicated by serum TSH enhancement. In all cases a supplement of l-thyroxine by itself was able to restore euthyroid TSH serum concentrations, suggesting that hypothyroidism in patients with partial epilepsy to whom CBZ had been administered requires a higher l-T4 substitutive regimen.

Circulating thyroid antibodies and thyroid function studies in children and adolescents with insulin-dependent diabetes mellitus

Significant high titres (1∶400–1∶25,600) of circulating thoroid microsomal antibodies (MCHA) were found in the sera of 5 out of 59 non-ketoacidotic, insulin-dependent diabetic (IDDM) patients (mean age 14.5 years). Among these five patients (four females, one male), all of whom were over 11 years, two also had thyroglobulin antibodies. Increased thyrotropin (TSH) response to TRH was found in 3/5 MCHA positive patients and in 3/54 without circulating MCHA. Serum thyroxine (T4) and free T4 (FT4) average values were significantly lower (P<0.01 and P<0.001) in diabetics (7.1±1.8μg/dl and 10.2±3.1 pg/ml, x±SD) as compared to normal sex and age matched controls (8.9±1.9 μg/dl and 12.2±2.2 pg/ml, respectively). T4 and FT4 values were inversely related to the duration of the disease. Subnormal T4 values were found in six (five females and one male) patients, four of whom had subnormal FT4 values. No patient had low triiodothyronine (T3) and high reverse T3 (rT3) values, i.e. none displayed the biochemical pattern of the ‘low T3 syndrome’ described with ketoacidotic status. This indicates also a satisfactory compensation of IDDM in all the patients. At the time of study no patient (including also those with circulating MCHA and TGHA and with TSH hyper-response to TRH) showed either thyroid size enlargement or clinical features of thyroid dysfunction including impaired growth and bone age retardation.

Serum TSH, T4, T3, FT4, FT3, rT3, and TBG in Youngsters with Non-Ketotic Insulin-Dependent Diabetes mellitus

Several parameters of thyroid function were studied in 112 non-ketoacidotic youngsters with insulin-dependent diabetes mellitus (IDDM). Levels of thyroxine (T4), reverse triiodothyronine (rT3), thyroxine-binding globulin (TBG) and T3 were lower than in controls, whereas FT4, and FT3 were normal. T4 levels in IDDM patients were positively related to T3, rT3 and TBG, and inversely related to haemoglobin A1 (HbA1). However, only 4 patients showed biochemical hypothyroidism (T4 less than 5 micrograms/100 ml), whereas their FT4, FT3 and thyroid-stimulating hormone (TSH) levels were normal. Concurrent variations of T3 and rT3 levels were found in IDDM patients; thus, their T3/rT3 ratios were stable or higher than in controls, indicating that peripheral deiodination of T4 is preferentially oriented to production of rT3 only during ketoacidosis. Although changes in thyroid function may reflect the degree of metabolic control of diabetes in a large population, the clinical usefulness of serum thyroid hormone measurements in an individual case still appears to be limited.

Effects of intravenous TRH on growth hormone and cortisol serum levels in children and adolescents with insulin dependent diabetes mellitus

The effects of an iv thyrotropin releasing hormone (TRH) bolus on serum growth hormone (GH) and Cortisol levels were evaluated in 59 children and adolescents with insulin dependent diabetes mellitus (IDDM) and in 24 healthy, age-matched control subjects. In the IDDM group GH baseline levels sharply rose within 30 min after TRH and successively normalized. On the contrary, TRH injection failed to affect GH serum concentrations in the control group. The GH increase after TRH in IDDM patients was positively correlated to age, but unrelated to other variables, such as sex, pubertal stage, duration of disease, glycemia, glycosylated hemoglobin, thyrotropin and T4 concentrations. Twenty-one out of 59 diabetics and only 1/24 controls exhibited a paradoxical GH response to TRH, arbitrarily defined as a precocious increase (within 30 min), of more than 100% with respect to the baseline value, associated with a GH peak > 10 ng/ml. Eighteen IDDM patients underwent a second TRH test 12 to 24 months later and substantially exhibited the same GH pattern documented the first time. The mechanism responsible for such anomalous GH responsiveness to TRH in IDDM is unclear. However, it cannot be attributed to a nonspecific stress reaction, as proven by the lack of a concomitant increase of Cortisol serum levels in the same subjects.

Effects of i.v. TRH on LH, FSH and GH serum levels in primary hypothyroid children

The occurrence of precocious puberty in children with primary hypothyroidism is a well recognized but poorly understood phenomenon. Several mechanisms have been proposed, but exceptions can be raised for each hypothesis (Lindsay et al, Am J Dis Child 134, 588, 1980). In 9/12 off-therapy primary hypothyroid children and adolescents (aged 1-16 yrs, 9 prepubertal and 3 pubertal) i.v. TRH (5μg/kg) injection elicited an evident increase of serum LH between 15 and 30 min, which exhausted within 90 min. Mean (± SEM) LH serum levels at 15 (2.22±0.45 ng/ml) and 30 min (2.22±0.43) were significantly (p< 0.005) higher as compared to the baseline ones (1.53±0.33). In the 3 pubertal hypothyroids LH was more than 100% of the basal concentrations. No significant increase of LH titers following i.v. TRH was appreciated in a control group of 24 children with constitutional short stature. According to previous reports a paradoxical GH response to TRH (GHΔ >7 ng/ml)was also recorded in 3/12 hypothyroids. On the contrary FSH serum levels were not substantially modified by TRH bolus, either in the patient or in the control group. An overlap in the pituitary hormonal feed-back mechanism had been hypothesized to explain the occurrence of precocious puberty in primary thyroid failure (Van Wyk and Grumbach, J Pediatr 57, 416, 1960). The nonspecific LH-releasing effect of TRH in our patients especially evident in the pubertal ones supports such hypothesis.

GH RESPONSE TO GRF IN HYPOTHYROID CHILDREN

Primary hypothyroidism has been reported Lo be associated with blunted GH responses to different stimuli which reverse to normal under thyroid hormone replacement. Whether such a pattern reflects an alteration in hypothalamic or pituitary mechanisims is unknown. In the present study we investigated GH response to i.v. (1 μg/Ky) GRF (1-29, Serono) in 7 untreated hypothyroid children (mean ±SD T4 4.0 ±1.4 μg/dl. T3 39.4 ± 10.0 ng/dl. TSH 113 ± 74 μUI/ml)and in the sane L-T4 substituted 7 patients (T4 15.0 ± 4.0, T3 165.3 ± 19.7, TSH 7.0 ± 0.5), who served as controls. Either baseline (8.1 ± 6.0 vs 3.9 ± 4.0 ng/ml)or GRF stimulated GH serum levels at 5 to 120 min did not significantly differ in the hypothyroid children than in the controls. Both GH max peak (51.5 ± 45.2 vs 28.5 ± 28.6; 2 p> 0.1) and GH Δ after GRF (43.4 ± 42.3 vs 25.0 ± 27.2; 2 p> 0.2)were only slightly but not significantly higher in the hypothyroids. No relationship was found between either GH peak or GH Δ and thyroid function tests in both groups. Our data indicate that, that somatotroph sensivity to GRF and pituitary GH reserve as well are not substantially impaired in hypothyroid subjects. The subnormal GH secretion associated with thyroid failure, therefore, may probably reflect a hypothalamic disorder. Such conclusion contrasts with that of a recent study in hypothyroid rats(Dieguez et al.J Endocr 109, 53, 1986).

Circulating Thyroid Autoantibodies in Children and Youngsters with Insulin Dependent Diabetes Mellitus (IDDM) are Not Predictive of Overt Autoimmune Thyroid Disease

Several studies unanimously indicate an increased prevalence of circulating thyroid antibodies in IDDM children,adolescents and young adults1–6.The clinical significance and the prognostic value of this finding are controvers1i al3 in that the risk of overt thyroid disease is high in white North-Americans 1,3 and negligible in European patients2,4–6 Aim of the present study is to evaluate the outcome of IDDM children and adolescents with circulating thyroid antibodies longitudinally followed during a 5-year period.

EFFECTS OF L-T4 THERAPY WITHDRAWAL ON GONADOTROPIN SERUM LEVELS IN L-T4 SUBSTITUTED HYPOTHYROID PATIENTS

Elevated serum LH levels and increased LH:FSH ratio which return to normal under L-T4 therapy are frequently observed in longstanding primary hypothyroidism and may account for the findings of precocious puberty and cystic ovaries in hypothyroids (Lindsay et al, Ai J Dis Child 134, 588, 1980). In 10 congenital hypothyroid subjects aged 7 to 18 yrs (6 prepubertal girls and 4 pubertal boys), L-T4 treatment was discontinued for a 3-week period in order to perform thyroid scan. All of them underwent iv LH-RH-test immediately before and 20 days after the therapy withdrawal. All the blood samples were processed in the same run. The shifting of TSH, T4 and T3 serum values froi the euthyroid to the hypothyroid range was accompanied in all the patients by a significant increase in both baseline LH (12.9±4.7 vs 6.3±2.5 mIU/ml, 2 p< 0.001) and PRL (22.6±11.7 vs 11.6±3.0 ng/ml, 2 p<0.05) plasia levels On the contrary LH peak after LHRH (22.5±7.9 vs 20.1±10.4) and either basal (2.4± ±1.5 vs 3.2± 2.1 mIU/ml) or stimulated (7.9±2.0 vs 6.8±2.0) FSH concentrations were not affected by L-T4 withdrawal. These results indicate that: a) an evident increase in LH serum levels precociously occurs in response to thyroid Failure; b) such increase does not reflect an enhanced sensitivity to LHRH; c) it may reflect anomalous LH reactivity to TRH (De Luca et al, Ped Res 18, 1222, 1984) or abnormal clearance (Lindsay et al).