Raymond L. Hintz

ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Mortality is predominantly related to the occurrence of cerebral oedema; only a minority of deaths in DKA are attributed to other causes. Cerebral oedema occurs in about 0.3–1% of all episodes of DKA, and its aetiology, pathophysiology, and ideal method of treatment are poorly understood. There is debate as to whether physicians treating DKA can prevent or predict the occurrence of cerebral oedema, and the appropriate site(s) for children with DKA to be managed. There is agreement that prevention of DKA and reduction of its incidence should be a goal in managing children with diabetes.

Plasma somatomedin and growth hormone values in children with protein-calorie malnutrition.

This study was undertaken to define the interrelationships of somatomedin, growth hormone, and an inhibitor of SM in protein-calorie malnutrition. Twenty-seven patients, eight to 60 months of age, were studied. Twenty-one well-nourished children acted as controls. SM was significantly depressed at Days 2 and 8 (p less than 0.01) but was not different from controls at Day 29 and 50. In ten out of 27 Day 2 samples and six out of 27 Day 8 samples an inhibitor was identified. When SM values were compared to simultaneous hGH levels, there was an inverse relationship. The low SM levels in the face of markedly elevated hGH levels suggests a functional block in the synthesis and/or release of SM.

Effect of Growth Hormone Treatment on Adult Height of Children with Idiopathic Short Stature

Background Short-term administration of growth hormone to children with idiopathic short stature results in increases in growth rate and standard-deviation scores for height. However, the effect of long-term growth hormone therapy on adult height in these children is unknown. Methods We studied 121 children with idiopathic short stature, all of whom had an initial height below the third percentile, low growth rates, and maximal stimulated serum concentrations of growth hormone of at least 10 microg per liter. The children were treated with growth hormone (0.3 mg per kilogram of body weight per week) for 2 to 10 years. Eighty of these children have reached adult height, with a bone age of at least 16 years in the boys and at least 14 years in the girls, and pubertal stage 4 or 5. The difference between the predicted adult height before treatment and achieved adult height was compared with the corresponding difference in three untreated normal or short-statured control groups. Results In the 80 children who have reached adult height, growth hormone treatment increased the mean standard-deviation score for height (number of standard deviations from the mean height for chronologic age) from -2.7 to -1.4. The mean (+/-SD) difference between predicted adult height before treatment and achieved adult height was +5.0+/-5.1 cm for boys and +5.9+/-5.2 cm for girls. The difference between predicted and achieved adult height among treated boys was 9.2 cm greater than the corresponding difference among untreated boys with initial standard-deviation scores of less than -2, and the difference among treated girls was 5.7 cm greater than the difference among untreated girls. Conclusion Long-term administration of growth hormone to children with idiopathic short stature can increase adult height to a level above the predicted adult height and above the adult height of untreated historical control children.

Serum insulin-like growth factors I and II concentrations and growth hormone and insulin responses to arginine infusion in children with protein-energy malnutrition before and after nutritional rehabilitation.

ABSTRACT: Serum insulin, growth hormone (GH), insulin-like growth factors (IGFs) I and II, cortisol, and albumin concentrations were measured in 15 children with kwashiorkor, 15 with marasmic-kwashiorkor, and 21 with marasmus, before and in the survivors, after nutritional rehabilitation, as well as in 10 underweight and eight normal Egyptian children. We also evaluated arginine-induced insulin and GH secretion. IGF-I concentrations were reduced in the three severely malnourished groups (0.07 ± 0.03, 0.05 ± 0.03, and 0.09 ± 0.09 U/ml, respectively) but returned to normal after refeeding. IGF-II concentrations were low in the kwashiorkor (175 ± 79 ng/ml), marasmic-kwashiorkor (111 ± 57 ng/ml), and marasmic children (128 ± 70.9 ng/ml) and returned to normal after nutritional rehabilitation. Basal GH levels were high in the three severely malnourished groups (21.9, 28.8, and 16.6 ng/ml, respectively) and returned to normal after refeeding (8.1, 6.5, and 6.0 ng/ml, respectively). GH responses to arginine were depressed in the three malnourished groups and improved significantly in marasmic-kwashiorkor and marasmic children after nutritional rehabilitation. Insulin responses to arginine were impaired in kwashiorkor, and marasmic-kwashiorkor children and improved significantly after refeeding. IGF-I levels correlated significantly with percent of expected weight (r=0.52, p<0.001), percent of expected height (r=0.42, p<0.001), and weight/ (height)2 index (r=0.34, p<0.01). IGF-I levels correlated positively with insulin levels (r=0.421, p<0.001) and negatively with cortisol concentrations (r=—0.400, p<0.001). It is suggested that effective lipolysis mediated by high GH and possibly low IGF levels, is an important adaptive mechanism to assure fuel (fatty acids) supply for metabolism of brain and peripheral tissues during nutritional deprivation.

Insulin-like growth factors I and II in evaluation of growth retardation

Plasma samples from 68 growth hormone (GH)-deficient children (provocative serum GH level less than 7 ng/ml), 44 normal short children, and 197 children with normal height were assayed by specific radioimmunoassays for the somatomedin peptides, insulin-like growth factors (IGF)-I and -II. Eighteen percent of the GH-deficient children had IGF-I levels within the normal range for age, whereas 32% of normal short children had low IGF-I levels. Low IGF-II levels were found in 52% of GH-deficient children, but also in 35% of normal short children. However, only 4% of GH-deficient children had normal plasma levels of both IGF-I and IGF-II. Furthermore, only 0.5% of normal children and 11% of normal short children had low plasma levels of both IGF-I and IGF-II. We conclude that plasma levels of either IGF-I or IGF-II overlap in GH-deficient and normal short children, but that the combination of radioimmunoassays may permit better discrimination among normal, normal short, and GH-deficient children.

Effect of Diabetes and its Control on Insulin-like Growth Factors in the Young Subject with Type I Diabetes

The influence of diabetes and its control on circulating levels of growth hormone and growth hormone-dependent, insulin-like growth factors (IGF) remains controversial. In the present study, the effect of a 1-wk period of intensive insulin therapy on growth hormone and IGF I and II has been determined in 19 young (age 13–22 yr), insulin-dependent (type I) subjects with diabetes mellitus. IGF I was low during conventional insulin therapy (198 ± 20 versus 438 ± 38 ng/ml in nondiabetic subjects, P < 0.001), and rose within the week of intensified treatment (to 255 ±15 ng/ml, P < 0.005), concomitant with a reduction in plasma glucose from 233 ± 16 to 110 ± 5 mg/dl. IGF I rose despite a significant fall in mean 24-h growth hormone levels from 14.1 ± 2.2 to 9.0 ± 1.2 ng/ml (P < 0.02). The mean IGF II value for the diabetic subjects (504 ± 39 ng/ml) was not significantly different from that of the nondiabetic control group (506 ± 30 ng/ml, P > 0.3) and was not altered by intensified therapy. However, four individual patients with very low IGF I also had depressed IGF II (248 ±16 ng/ml), which was corrected (to 377 ± 35 ng/ml) with improved metabolic control. These data suggest that elevated growth hormone levels in poorly controlled diabetes are ineffective in IGF I generation and that this defect is at least partially corrected by acute improvement in control. The rise in IGF I levels accompanying intensive insulin treatment may suppress the excessive secretion of growth hormone. IGF II levels appear to be affected only by the most severe reductions of growth hormone activity.

Normal ranges for immunochemiluminometric gonadotropin assays

OBJECTIVE We sought to establish normative data for spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays (ICMA) in children and adolescents. METHODS Random serum samples were obtained from 375 normal subjects (0.1 to 17.7 years, 230 female subjects). Intravenous GnRH stimulation tests were performed in 41 normal subjects (4.8 to 18 years, 20 female subjects). Normal ranges were calculated by age and Tanner stage. Immunochemiluminometric assays of LH and FSH concentrations were compared with levels obtained by a sensitive immunofluorometric assay and a less sensitive radioimmunoassay. RESULTS Random gonadotropin concentrations in normal children followed the pattern of transient elevation in infancy, low but measurable prepubertal levels, and markedly increased values at puberty. Spontaneous LH levels were higher in male infants but were not statistically different in boys and girls after infancy. Mean prepubertal LH was 0.04 +/- 0.04 IU/L (n = 66), rising 100-fold during puberty. Spontaneous FSH levels were much higher than LH values, were higher in female infants, and rose threefold at puberty. Peak GnRH-stimulated LH was identical in prepubertal boys and girls (1.8 +/- 1.3 IU/L, n = 17) and increased 20-fold at puberty. Mean peak GnRH-stimulated FSH was highest in prepubertal female subjects. Luteinizing hormone values measured by ICMA and immunofluorometric assay were highly correlated, but radioimmunoassay levels diverged markedly from ICMA levels at lower concentrations. Because absolute levels were higher, FSH values correlated adequately in the three assays throughout the normal physiologic range. CONCLUSIONS Measurement of LH by ICMA is much more sensitive than older assay methods. Spontaneous LH can be accurately measured by ICMA to the very low levels present in normal prepubertal children, providing a potentially important biochemical discriminator of pubertal status. An ICMA GnRH-stimulated LH level greater than 5 IU/L is suggestive of maturing gonadotropin secretion. The ICMA LH assays provide significant enhancement in sensitivity; these assays should be used when levels may be low, and by their accuracy may reduce the time and expense of testing procedures.

Effects of Prolonged Dopamine Infusion on Anterior Pituitary Function in Normal Males

The correlation between acute and chronic somatomedin (SM) response to hGH treatment of hypopituitary dwarfism and the value of SM levels in predicting growth rates were investigated in 20 children with GH deficiency. Plasma samples for SM determinations were obtained before treatment, 12–14 h after each of 4 daily injections of hGH (0.1 U/kg) and after 6 months of hGH (0.1 U/kg 3 times per week). Mean plasma SM-C levels by placental membrane radioreceptor assay rose from 0.39 ± 0.05 U/ml (mean ± SEM) on day 1 to 1.18 ± 0.14 U/ml on day 5 and measured 0.95 ± 0.12 U/ml at 6 months. By RIA, mean plasma SM-C levels rose from 0.19 ± 0.03 U/ml on day 1 to 0.82 ± 0.11 U/ml on day 5 and measured 0.79 ± 0.11 U/ml at 6 months. However, individual SM responses to acute and chronic hGH treatment were highly variable, with 7 children raising SM-C levels above 1 U/ml (RIA) by day 5, while 3 children maintained SM levels less than 0.1 U/ml. The latter 3 had persistently low SM levels at 6 months (<0.20 U/ml), despite g...

Insulin-Infusion-Pump Treatment of Diabetes: Influence of Improved Metabolic Control on Plasma Somatomedin Levels

We examined whether changes in somatomedin accompany those seen in glucose and growth hormone during treatment with the insulin-infusion pump. somatomedin levels in eight insulin-dependent diabetics (13 to 29 years of age) were measured before and after 16 weeks of outpatient insulin-pump treatment, which lowered mean glucose from 245 +/- 21 to 100 +/- 5 mg per deciliter and total glycosylated hemoglobin from 16.2 +/- 1.2 to 9.7 +/- 0.3 per cent (mean +/- S.E.M.). During conventional insulin therapy, both total somatomedin and somatomedin C were within the normal range, despite elevations in growth hormone. Pump treatment resulted in a 70 to 75 per cent increase in both total somatomedin and somatomedin C (P less than 0.05) and a fall in growth-hormone concentrations. In the two growing adolescents, growth velocity doubled during 13 to 15 months of pump treatment. Our data suggest that the improved insulin delivery or metabolic control increases somatomedin levels despite a decrease in growth hormone. Thus, insulin-pump treatment may be useful in optimizing growth in diabetic children.

Prospective clinical trial of human growth hormone in short children without growth hormone deficiency

Ten unselected, apparently healthy short children who were capable of normal growth hormone secretion were given human growth hormone (0.1 U/kg 1M thrice weekly) for 6 months to determine whether such treatment might lead to an increase in growth velocity. During treatment, all patients increased their growth rate (from 4.3 +/- 0.3 cm/yr to 7.4 +/- 0.5 cm/yr P less than 0.001). No adverse effects were detected. During the four-day IGF generation test, IGF I and IGF II levels rose significantly from 0.32 +/- 0.04 U/ml to 0.62 +/- 0.13 U/ml and from 279 +/- 36 ng/ml to 434 +/- 49 ng/ml, respectively. However, the growth response was not predicted by either the acute rise in IGF I or that in IGF II. Human growth hormone in standard doses may be capable of inducing accelerated growth in some short children without growth hormone deficiency. Measurements of IGF I and II cannot be used to predict which children will respond.