Alpha 2 HS-glycoprotein levels in children with protein-energy malnutrition and infections

Serum alpha 2 HS-glycoprotein levels were studied, using the single-radial immunodiffusion method, in 39 severely malnourished children (22 kwashiorkor, 17 marasmus) of whom 15 (8 kwashiorkor, 7 marasmus) were infected and 24 (14 kwashiorkor, 10 marasmus) had no signs of infection. Thirty-two well-nourished children, 16 of whom were infected, served as controls. The uninfected controls had higher serum alpha 2 HS-glycoprotein levels than the uninfected kwashiorkor (82.0 +/- 14.7; 57.0 +/- 15.8; p less than 0.001) and marasmic children (82.0 +/- 14.7; 45.0 +/- 13.9; p less than 0.001). Infection was associated with a significant decrease in the mean serum alpha 2 HS-glycoprotein levels in the well-nourished (82.0 +/- 14.7; 57.0 +/- 7.7; p less than 0.001) and kwashiorkor (57.0 +/- 15.8; 34.0 +/- 20.4; p less than 0.02) children, while no such decrease was observed in the marasmic children. While the mean serum glycoprotein level in the infected controls was higher than that in the infected kwashiorkor children (57.0 +/- 7.7; 34.0 +/- 20.4; p less than 0.02), it was comparable to that in the infected marasmic children (57.0 +/- 7.7; 50.0 +/- 11.6; p greater than 0.05). Furthermore, the mean alpha 2 HS-glycoprotein level in the infected malnourished children was higher in marasmus than in kwashiorkor (50.0 +/- 11.6; 34.0 +/- 20.4; p greater than 0.05); this difference was, however, not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Attenuation of spontaneous, nocturnal growth hormone secretion in children with hypothyroidism and its correlation with plasma insulin-like growth factor I concentrations

To define further the alterations in growth hormone (GH) secretion that occur in childhood hypothyroidism, we quantified spontaneous nocturnal secretion in seven patients with primary hypothyroidism. We examined the relationship between plasma insulin-like growth factor I (IGF-I) and GH secretory profile in each patient before and during therapy with L-thyroxine. In contrast to the results of previous studies that used pharmacologic tests of GH release, spontaneous GH secretion was consistently attenuated in the hypothyroid state. Mean nocturnal GH levels were reduced by 58% (1.48 +/- 0.38 ng/ml, mean +/- SEM) in comparison with values obtained during L-thyroxine therapy (3.54 +/- 0.71 ng/ml, p less than 0.01). Coincident with the reduced levels of GH, plasma IGF-I concentrations were lower in patients before therapy (0.46 +/- 0.20 U/ml) compared with concentrations during therapy (1.50 +/- 0.34 U/ml, p less than 0.01). In treated, euthyroid patients, GH and IGF-I levels were equivalent to those of normal children. The excellent correlation (r = 0.77) between plasma IGF-I and mean nocturnal GH concentrations indicates that reduced plasma IGF-I levels in hypothyroidism probably result from suppressed GH secretion.     

Basal and stimulated levels of growth hormone, insulin-like growth factor-I (IGF-I), IGF-I binding and IGF-binding proteins in beta-thalassemia major

A significant percentage of children with beta-thalassemia major shows retardation in longitudinal growth as they progress towards puberty due to skeletal dysplasia, endocrine gland hypofunction or trace element deficiencies. The aim of this study was to evaluate GH/IGF-I secretion and action in prepubertal patients with beta-thalas-semia major. Eight prepubertal patients with short stature (group A) and seven prepubertal patients with normal stature (group B) were studied. Basal and stimulated (after administration of the hexapeptide Hexarelin) GH levels were measured with IRMA (Nichols); IGF-I and IGFBP-3 levels were measured with RIA (Nichols). IGF-I binding proteins (IGFBPs) were analyzed qualitatively with Western ligand blot. IGF-I binding to B-lymphocytes of the patients was also measured with competitive binding studies using human recombinant IGF-I and 125I-IGF-I (Amersham). Basal GH levels did not differ statistically between the groups. Peak GH levels after Hexarelin stimulation test were higher in group A (A: 27.9 +/- 15.6 ng/ml vs B: 9.1 +/- 4.7 ng/ml) (Wilcoxon test, p < 0.05). IGF-I levels in the two groups were low-normal and comparable (A: 168.0 +/- 81.6 ng/ml vs B: 126.6 +/- 25.5 ng/ml). IGFBP-3 levels were low in both groups (A: 1.21 +/- 0.27 microg/ml vs B: 1.08 +/- 0.20 microg/ml). Western ligand blot did not reveal any discernible difference in IGFBPs. However, IGF-I binding on B-lymphocytes was at least 20% lower in group A compared to group B (t-test, p < 0.01). IGF-I binding inversely correlated with peak GH levels (r = -0.54, p < 0.05). Patients in group A were older and chronological age correlated with IGF-I levels (r = 0.53, p < 0.05) whereas it inversely correlated with IGF-I binding (r = -0.63, p < 0.05). Moreover, patients in group A had higher ferritin levels. No correlation was found between ferritin levels, desferrioxamine dose/compliance or liver enzyme levels and the parameters of the GH axis studied. However, desferrioxamine dose x years correlated with IGFBP-3 (r = 0.56, p < 0.05) and correlated inversely with IGF-I binding (r = -0.74, p < 0.01). In conclusion, we have shown adequate GH secretion, higher secretive capacity after the administration of Hexarelin and lower IGF-I binding in prepubertal beta-thalassemic patients with short stature. Whatever the cause, reduced IGF-I action has to be considered when treating beta-thalassemic patients with short stature.     

Spontaneous and provoked growth hormone (GH) secretion and insulin-like growth factor I (IGF-I) concentration in patients with beta thalassaemia and delayed growth

Growth retardation in children with thalassaemia major is multifactorial. We studied the growth hormone (GH) response to provocation by clonidine and glucagon, measured the circulating concentrations of insulin, insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP3), and ferritin, and evaluated the spontaneous nocturnal (12 h) GH secretion in prepubertal patients with thalassaemia and age-matched children with constitutional short stature (CSS) (height SDS < -2, but normal GH response to provocation). The anatomy of the hypothalamic pituitary area was studied in patients with abnormal GH secretion using MRI scanning. Children with thalassaemia had significantly lower peak GH response to provocation by clonidine and glucagon (8.8 +/- 2.3 micrograms/l and 8.2 +/- 3.1 micrograms/l respectively) than did controls (17.6 +/- 2.7 micrograms/l and 15.7 +/- 3.7 micrograms/l respectively). They had significantly decreased circulating concentrations of IGF-I and IGFBP3 (68.5 +/- 19 ng/ml and 1.22 +/- 0.27 mg/l respectively) compared to controls (153 +/- 42 ng/ml and 2.16 +/- 0.37 mg/l respectively). Seven of the thalassaemic children had a GH peak response of < 7 micrograms/l after provocation. Those with a normal GH response after provocation also had significantly lower IGF-I and IGFBP3 concentrations than controls. Analysis of their spontaneous nocturnal GH secretion revealed lower mean (2.9 +/- 1.77 micrograms/l) and integrated (2.53 +/- 1.6 micrograms/l) concentrations compared to controls (4.9 +/- 0.29 micrograms/l and 5.6 +/- 0.52 micrograms/l respectively). Five of them had mean nocturnal GH concentration < 2 micrograms/l and four had maximum nocturnal peak below 10 micrograms/l. These data denoted defective spontaneous GH secretion in some of these patients. MRI studies revealed complete empty sella (n = 2), marked diminution of the pituitary size (n = 4), thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2), and evidence of iron deposition in the pituitary gland and midbrain (n = 7) in those patients with defective GH secretion (n = 9). Serum ferritin concentration was correlated significantly with the circulating IGF-I (r = -0.47, p < 0.01) and IGFBP3 (r = -0.43, p < 0.01) concentrations. These data prove a high prevalence of defective GH secretion in thalassaemic children associated with structural abnormality of their pituitary gland.     

A comparison of fasting plasma insulin and growth hormone concentrations in marasmic, kwashiorkor, marasmic-kwashiorkor and underweight children.

Fasting plasma insulin and growth hormone concentrations were measured in 24 marasmic, 11 kwashiorkor, 16 marasmic-kwashiorkor, and 4 underweight children. Hormone measurements were made by a special modification of the Hales and Randle double antibody immunoassay with increased sensitivity in the concentration range 0-25 micronU/ml. Fasting plasma insulin was low in marasmus, kwashiorkor, and marasmic-kwashiorkor children, and increased to normal levels after recovery. Fasting plasma growth hormone was elevated in all groups during malnutrition and was significantly decreased to normal levels after recovery. There were no significant differences in plasma insulin or growth hormone levels between the different clinical types of severe protein energy malnutrition. These hormonal changes in severe protein energy malnutrition are of complex and not fully understood etiology. However, recovered children appear to have a hormonal pattern similar to that described in normal control infants and children.     

Linear growth, growth-hormone secretion and IGF-I generation in children with neglected hypothyroidism before and after thyroxine replacement

We studied growth hormone (GH) stimulation and insulin-like growth factor -I (IGF-I) generation tests in 15 children with neglected congenital hypothyroidism (CH) (age = 6.4 +/- 4.2 years) and measured their growth parameters for >1 years after starting thyroxine (T4) replacement. One year after treatment, height SDS (HtSDS) increased from -4.3 +/- 2.5 to -2.7 +/- 2.3. Peak GH response to clonidine increased from 3.2 +/- 1.2 ng ml(-1) to 7.62 +/- 1.38 ng ml(-1) after treatments. Basal and peak IGF-I response to GH increased from (34.66 +/- 17.3 ng ml(-1) and 58.4 +/- 36.99 ng ml(-1), respectively) before treatment to (130.6 +/- 97.8 ng ml(-1) and 193.75 +/- 122.5 ng ml(-1), respectively). HtSDS increments were correlated significantly with basal free T4 concentrations (r = 0.622, P < 0.01). In summary, after long period of hypothyroidism, T4 replacement produced significant, although incomplete, catch-up growth through a partial recovery of GH- IGF-I axis.     

Effect of zinc supplementation on growth hormone secretion, IGF-I, IGFBP-3, somatomedin generation, alkaline phosphatase, osteocalcin and growth in prepubertal children with idiopathic short stature

Controversy exists about the effect of zinc on growth and the GH-IGF system. Zinc supplementation has been shown to stimulate linear growth in zinc-deficient children. However the mechanism of this effect has not been well characterized. Furthermore, the effect of zinc supplementation on non-zinc-deficient short children is unknown. We investigated the effect of zinc supplementation on endogenous GH secretion, serum IGF-I and IGFBP-3 concentrations, IGF-I and IGFBP-3 generation in response to exogenous GH, bone formation markers, and linear growth of non-zinc-deficient children with idiopathic short stature. We analyzed prospectively serum zinc, IGF-I, IGFBP-3, alkaline phosphatase, osteocalcin, and GH response to clonidine test, and performed a somatomedin generation test before and 6 weeks after zinc supplementation in 22 (16 M, 6 F) prepubertal children with idiopathic short stature. Serum IGF-I increased from 67.4+/-70.6 to 98.2+/-77.3 ng/ml (p <0.001), IGFBP-3 from 2326+/-770 to 2758+/-826 ng/ml (p <0.001), alkaline phosphatase from 525+/-136 to 666+/-197 U/l (p <0.0001), and osteocalcin from 16.8+/-10.6 to 25.8+/-12.8 ng/ml (p <0.05) after zinc supplementation despite there being no difference in GH response to clonidine after zinc supplementation (peak GH 11.6+/-6.9 vs 13.4+/-7.8 ng/ml, GH area under the curve during clonidine test 689+/-395 vs 761+/-468, NS). Percent change in IGF-I and IGFBP-3 during the somatomedin generation test was not significantly affected by zinc supplementation (118% vs 136% and 57% vs 44%, respectively). There was no significant correlation between percentage increase in zinc levels and percentage increase in parameters tested. Height SDS or weight SDS did not improve significantly in 17 patients who continued on zinc supplementation for at least 6 months (6-12 months) (-2.59 vs -2.53 SDS and -1.80 vs -1.67 SDS, respectively). Zinc supplementation increased basal IGF-I, IGFBP-3, alkaline phosphatase and osteocalcin without changing GH response to clonidine. Zinc supplementation did not affect sensitivity to exogenous GH as tested by IGF-I and IGFBP-3 generation test. These results suggest a direct stimulatory effect of zinc on serum IGF-IGFBP-3, alkaline phosphatase and osteocalcin. Despite improvements in the above parameters, zinc supplementation to children with idiopathic short stature with normal serum zinc levels did not significantly change height or weight SDS during 6-12 months follow-up.     

Growth hormone deficiency impedes the rise in plasma insulin-like growth factor I levels associated with precocious puberty

We tested the hypothesis that growth hormone (GH) mediates the rise in insulin-like growth factor I (IGF-I) concentrations in children with precocious puberty. We studied three groups of patients. Group 1 included six children with GH deficiency and precocious puberty (precocious GH-deficient); group 2 included 10 GH-sufficient patients with idiopathic true precocious puberty (precocious GH-sufficient); and group 3 included 9 prepubertal children with GH deficiency (prepubertal GH-deficient). Growth rates, pubertal status, and plasma IGF-I concentrations were determined at regular intervals. The precocious children with GH deficiency had a mean (+/- SD) growth rate of 7.2 +/- 2.1 significantly below that of the precocious GH-sufficient patients (10.5 +/- 2.5 cm/yr, p less than 0.05) but above that of the prepubertal GH-deficient children (3.9 +/- 1.4 cm/yr, p less than 0.05). The mean IGF-I concentration in the precocious GH-deficient children was 0.77 +/- 0.39 U/ml, significantly lower than the mean level of 2.2 +/- 0.67 U/ml in the precocious GH-sufficient patients (p less than 0.01). However, precocious GH-deficient patients had significantly higher IGF-I values than the prepubertal GH-deficient children (0.24 +/- 0.10 U/ml, p less than 0.05). IGF-I values did not rise with the onset of precocious puberty in four of the precocious GH-deficient children evaluated before and after the development of precocious puberty. However, three patients who began GH treatment did have a rise in plasma IGF-I concentrations to levels of 1.2, 3.4, and 3.7 U/ml, respectively. These findings are compatible with the concept that sex steroids increase IGF-I levels in precocious puberty primarily by increasing GH production. A small but direct effect of sex steroids on IGF-I production may also exist. The onset of precocious puberty in children with organic GH deficiency may mask the abnormal growth pattern of these children and delay diagnosis; determinations of plasma IGF-I concentrations may be helpful in assessing the GH status of these patients.     

Diagnostic significance of urinary growth hormone measurements in children with growth failure: correlation between serum and urine growth hormone

Twelve-h overnight urine and serum samples obtained simultaneously at 20-min intervals were assayed for growth hormone (GH). Ninety-one children, 5 to 16 y (Tanner stage 1 to 3) participated; group 1 were healthy children, group 2 were children with organic GH deficiency, and group 3 had idiopathic growth failure and normal GH stimulation tests. Serum pool GH concentrations in group 1 were similar to those in group 3 (3.3 +/- 0.3 versus 3.4 +/- 0.2 micrograms/L); group 2 had significantly lower GH concentrations (1.6 +/- 0.2 micrograms/L). Plasma IGF-I levels were significantly greater in groups 1 (14.2 +/- 2.6 nmol/L, p less than 0.001) than in groups 2 and 3 (2.6 +/- 0.5 and 5.5 +/- 0.7 nmol/L, respectively). Urinary GH (mean +/- SEM) standardized for body weight (micrograms/kg) in group 1 (0.31 +/- 0.02) was significantly greater than in group 2 (0.14 +/- 0.01) and group 3 (0.20 +/- 0.01). However, when expressed as microgram/mol creatinine, the output of GH was similar in group 1 (4.0 +/- 0.3) and group 3 (3.4 +/- 0.3); both groups had significantly greater output compared to group 2 (1.3 +/- 0.2). Urinary IGF-I (nmol/kg) in group 1 (0.22 +/- 0.02) was significantly greater than in group 2 (0.12 +/- 0.01) or group 3 (0.07 +/- 0.01). Urinary GH correlated with serum pool GH concentration (r = 0.64, p less than 0.001). Although urinary GH output reflects endogenous GH secretion, the overlap between groups 1 and 3 precludes using urinary GH measurements as a diagnostic test for GH deficiency in children with idiopathic growth failure.     

Chronic hypoxemia leads to reduced serum IGF-I levels in cyanotic congenital heart disease

Cyanotic congenital heart disease in children commonly causes more pronounced growth retardation in comparison with acyanotic congenital heart disease. Chronic hypoxemia has been suggested as the cause of poor growth in these patients, but the relationship between serum IGF-I levels and chronic hypoxemia is unclear. Serum IGF-I concentrations, oxygen saturation and nutritional status were evaluated in 29 patients with cyanotic congenital heart disease, and serum IGF-I levels were compared with a group of 20 well-nourished, age-matched control children to assess the relationship between IGF-I levels and chronic hypoxemia. The nutritional status of each patient was determined by using anthropometric parameters and calorie and protein intake ratios. The patients were divided into malnourished and well-nourished groups (21 and 8 patients, respectively) according to their nutritional status. Serum IGF-I concentrations were measured in the two patient groups and the controls. The malnourished group had the lowest IGF-I levels (48.14 +/- 21.8 ng/ml, p<0.05). However, the well-nourished group's IGF-I levels were significantly lower than the control subjects' despite improved nutritional status (85.5 +/- 30.2 and 107 +/- 19.7 ng/ml, respectively, p<0.05). In addition, we found a positive correlation between serum IGF-I levels and oxygen saturation of the patients (r=0.402, p<0.05). These findings indicate that chronic hypoxemia has a direct or indirect effect to reduce serum IGF-I concentrations and this may be a cause of the increased growth failure in patients with cyanotic congenital heart disease.     

Growth parameters and endocrine function in relation to echocardiographic parameters in children with ventricular septal defect without heart failure.

To determine the effect of ventricular function, size of ventricular septal defect (VSD), and endocrine function on linear growth in children with VSD, we studied 88 children with VSD over a period of 1 year. Growth was assessed by determining the height standard deviation scores (HtSDS) and growth velocity (GV) every 4 months. Two hundred age-matched normal children served as controls for the growth data. Endocrine evaluation was performed in 30 randomly selected children with VSD, and 20 age-matched children with constitutional delay of growth (CSS). Growth hormone (GH) response to clonidine provocation was evaluated and circulating free thyroxine (FT4) and insulin-like growth factor-I (IGF-I) concentrations measured. Echocardiographic evaluation of the different cardiac parameters including shunt size and shunt fraction (Qp/Qs) was performed using a colour-coded echodoppler. The HtSDS, body mass index (BMI), and mid-arm circumference (MAC) of children with VSD were significantly decreased compared to those for the normal control group. The dietary intake evaluated by the recall method, appeared to be adequate in the majority of these children (83/88). IGF-I concentrations were reduced in children with VSD (87.5 +/- 29 ng/ml) versus normal age-matched children (169 +/- 42 ng/ml). Basal and clonidine-stimulated GH concentrations were significantly higher in children with VSD (4.6 +/- 2.1 microg/l and 28.8 +/- 7.9 microg/l respectively) versus controls (17.8 +/- 4.2 microg/l). In these patients (n = 88) the HtSDS was correlated negatively with the size of the shunt (r = -0.793, p < 0.001), shunt fraction (Qp/Qs) (r = -0.76, p < 0.001), pulmonary mean gradient (r = -0.4, p = 0.006), and pulmonary maximum velocity (r = -0.32, p = 0.02). Growth velocity (GV) was correlated negatively with pulmonary maximum gradient (r = -0.3, p = 0.02), pulmonary maximum velocity (r = -0.37, p = 0.007), and pulmonary stroke volume (Qp) (r = -0.345, p = 0.01). The BMI and IGF-I concentrations were correlated significantly with the size of the shunt (r = -0.453, p < 0.01), Qp/Qs (r = -0.432, p < 0.01), HtSDS (r = 0.565, p < 0.01), and BMI (r = 0.435, p < 0.01). It appears that in patients with VSD, the size of the left-to-right shunt and the abnormal hemodynamics in the pulmonary circulation are important factors in the etiology of impaired growth. It is suggested that the hypermetabolic status of these patients compromise nutrition and this decreases IGF-I synthesis with subsequent slowing of linear growth and weight gain.     

Differential impact of simple childhood obesity on the components of the growth hormone-insulin-like growth factor (IGF)-IGF binding proteins axis

Simple childhood obesity is characterized by normal or even accelerated growth in spite of reduced growth hormone (GH) secretion. There are conflicting reports on the effects of obesity upon components of the GH-insulin-like growth factor-I (IGF-I)-IGF binding proteins (IGFBPs) system. In the present study we aimed to determine GH, IGF-I, IGFBP-3 and IGFBP-2 as well as some of the less explored components of this axis (IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments, and total acid labile subunit [ALS]) in 22 obese and 17 age-matched control children. We also evaluated not only total GH binding protein (GHBP) serum levels but also GHBP bound to GH (complexed) in both groups. Obese and control groups strongly differed in BMI (obese: 4.7 +/- 0.36 vs control: 0.37 +/- 0.25 SDS, p <0.0001). In the obese group, we found lower GH serum levels, but normal serum levels of GH-GHBP complex, IGF-I, IGFBP-3, IGF-I/IGFBP-3 molar ratio, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Obese children presented higher total circulating GHBP (6.0 +/- 0.44 vs 2.9 +/- 0.29 nmol/l, p <0.001) and insulin levels (10.5 +/- 1.5 vs 5.1 +/- 0.8 mU/l, p <0.001), while IGFBP-2 (4.6 +/- 0.5 vs 6.6 +/- 0.7%, p <0.05) and the ratio IGFBP-2/IGF-I (0.032 +/- 0.019 vs 0.095 +/- 0.01, p = 0.013) were lower than in controls. BMI and insulin were directly, and IGFBP-2 serum levels inversely, correlated to total GHBP serum levels when multiple regression analysis was performed (r = 0.74, p <0.001). By stepwise regression analysis, insulin (r = -0.37, p <0.05) and BMI (r = -0.52, p <0.01) inversely determined IGFBP-2. In summary, obese children present normal growth in spite of reduced GH secretion, probably because the combination of increased total GHBP and normal GH-GHBP complex serum levels (suggesting increased GH receptor [GHR] number and a normal serum GH reservoir, respectively) allow for the achievement of normal levels of IGF-I, IGFBP-3, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Reduced IGFBP-2 serum levels and a lower ratio of IGFBP-2/IGF-I in obese children may suggest an increase of tissue IGF-I bioavailability, thus promoting its action. Normal IGF-I and GH availability may be contributing to maintain normal growth in obese children.     

Inflammatory and growth mediators in growing preterm infants

Little is understood about the optimal balance between IGF-I and antagonistic inflammatory mediators, such as IL-6, in growing preterm infants. Using a prospective cohort study, we investigated the relationship between postnatal growth of preterm infants and key growth and inflammatory mediators. We studied 51 stable, growing preterm infants (mean gestational age: 27.8 +/- 0.4 weeks, mean birth weight: 1,032.8 +/- 50.6 g). IL-6 and IL-1ra (reflecting stress/ inflammation) and IGF-I and GHBP (reflecting anabolic activity and GH sensitivity) were measured at enrollment and discharge using ELISA. During the observation period (mean 6.1 +/- 0.34 weeks) there was a significant increase in weight (1,396 +/- 81 g, p < 0.0001). IGF-I increased from 46.6 +/- 4.1 to 88.7 +/- 5.2 ng/ml (p < 0.001). In contrast, IL-6 decreased from 9.5 +/- 1.0 to 2.3 +/- 0.34 pg/ml (p <0.001) and IL-1ra from 6,042 +/- 362 to 4,851 +/- 365 ng/ml (p = 0.007). GHBP increased from 65.8 +/- 6.7 to 82.5 +/- 7.9 ng/ml (p = 0.003). IL-6 was inversely correlated with IGF-I (p < 0.001). In addition, a multiple regression model showed IGF-I levels correlated positively and IL-6 levels inversely with various parameters of growth. Growth in preterm infants is characterized by increases in IGF-I and GHBP with simultaneous decreases in IL-6 and IL-1ra. Efforts to optimally balance inflammatory and growth mediators may benefit somatic growth in infants very early in life.     

Evaluation of insulin-like growth factor (IGF)-I and IGF binding protein-3 generation test in short stature

BACKGROUND: Differentiation between growth hormone deficiency (GHD) and idiopathic short stature (ISS) based on GH tests and basal IGF-I and IGFBP-3 levels may be difficult. The aim of this study was to evaluate the role of pharmacological GH tests, IGF-I and IGFBP-3 generation test and height velocity off-treatment in the evaluation of GHD and ISS. METHODS: Thirty-three (17 M, 16 F) prepubertal short (height SDS < -2) children were divided into two groups: Group 1 (n = 19) with peak GH level <10 tg/l (GHD) and Group 2 (n = 14) GH > or =10 microg/l in two sex steroid primed pharmacological GH tests. Having excluded other diagnoses, Group 2 was regarded as having ISS. The generation test was performed concomitantly (0.1 IU/kg GH s.c. for 4 days) with IGF-I and IGFBP-3 measured on the 4th day in both groups. The patients were followed for a year for height velocity (HV). RESULTS: Group 1 and 2 had comparable height SDS (-2.3 +/- 0.4 and -2.3 +/- 0.3) at comparable ages (7.8 +/- 2.8 and 7.0 +/- 2.7 yr). Although the deltaIGF-I response was low (<2.0 nmol/l 115 ng/ ml]) in seven (37%) children in the GHD group, all GHD patients with low height velocity had adequate (> or =14 nmol/I [400 ng/ml]) deltaIGFBP-3 response. deltaIGFBP-3 in the generation test showed a negative correlation with HV (p = 0.021, r = -0.570) and also with basal IGFBP-3 (p <0.001, r = -0.743) in the GHD group. In the ISS group, deltaIGF-I and deltaIGFBP-3 responses were low in 31% and 7%, respectively, and the correlation between basal IGF-I, IGFBP-3 and HV and between delta values in the generation test were significantly positive, pointing to a difference in the growth response of these children. CONCLUSION: In the GHD group, based on pharmacological tests, an adequate deltaIGFBP-3 response in the generation test predicts poor height velocity at follow up and thus strengthens the diagnosis of true GHD.     

Insulin-like growth factor I in substrate-deprived, growth-retarded fetal rats

Plasma, amniotic fluid, and tissue concentrations of IGF-I were examined in nutritionally deprived, growth-retarded fetal rats to determine whether IGF-I concentration serves as a marker for nutritional status. Growth retardation was induced by 72 h of maternal fasting. Twenty-three control and 17 growth-retarded fetuses were individually analyzed and compared. Plasma IGF-I concentrations were significantly lower in test compared with control animals (test 56.8 +/- 14.9, control 87.4 +/- 17.5 ng/mL, p less than 0.01). Amniotic fluid IGF-I concentrations were not different (test 14.0 +/- 8.7, control 12.2 +/- 2.6 ng/mL). IGF-I concentrations obtained from both placental and hepatic tissues were lower in test compared with control animals [placenta: test 293 +/- 25 versus control 655 +/- 114 ng/g (p less than 0.001); hepatic: test 173 +/- 38 versus control 230 +/- 51 ng/g (p less than 0.01)]. Reductions in fetal, placental, and hepatic weights in test animals were more closely related to changes in placental IGF-I concentration than to either plasma or hepatic IGF-I concentrations. We conclude that fetal plasma IGF-I is a valuable marker for intrauterine substrate deprivation and that the growth-retarded rat fetus is accurately identified and specifically characterized by a low placental concentration of extractable IGF-I.     

Serum levels of insulin-like growth factor (IGF)-I, free IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3 and insulin in obese children.

In simple obesity, spontaneous and stimulated growth hormone (GH) secretions are diminished. However, this diminished GH secretion does not result in decreased somatic growth in obese children. Although the increased insulin level, low insulin-like growth factor binding protein (IGFBP)-1 and the resulting increase of bioavailability of insulin-like growth factor I (IGF-I) have been suggested as being involved, the exact mechanism has not yet been established. We investigated serum IGF-I, free IGF-I, IGFBP-1, IGFBP-3 and insulin levels in 36 obese and 39 non-obese healthy children. Insulin and IGFBP-3 were significantly higher in the obese group than in the control group (p < 0.05, p = 0.001, respectively). IGF-I, free IGF-I, free IGF-I/IGF-I and IGFBP-1 levels in the obese children were not significantly different from those in the control group. A positive correlation was found between body mass index (BMI) and IGF-I in the obese children (r = 0.30, p = 0.05). IGFBP-3 levels correlated positively with IGF-I (r = 0.44, p < 0.005), and free IGF-I levels (r = 0.37, p = 0.05) in the obese children. A negative correlation was found between IGFBP-1 and insulin levels (r = -0.30, p = 0.05) in the obese children. We concluded that normal growth in obese children might be maintained through normal IGF-I and increased IGFBP-3 levels, which are stimulated by increased insulin levels or nutritional factors or by increased responsiveness to GH.     

Insulin-like growth factor I response during nutritional rehabilitation of persistent diarrhoea.

OBJECTIVE: Evaluation of nutritional recovery, intestinal permeability, and insulin-like growth factor I (IGF-I) response in malnourished children with persistent diarrhoea and their relation to concomitant systemic infection(s). STUDY DESIGN: Open study of severely malnourished children (aged 6-36 months) with persistent diarrhoea (>/= 14 days) admitted for nutritional rehabilitation with a standardised rice-lentil and yogurt diet. Successful recovery was defined prospectively as overall weight gain (> 5 g/kg/day) with a reduction in stool output by day 7 of treatment. Data on coexisting infections and serum C reactive protein (CRP) were collected at admission. RESULTS: Of 63 children, 48 (group A) recovered within seven days of dietary treatment. These children had a significant increase in serum IGF-I (DeltaIGF-I%) and, in contrast to serum prealbumin and retinol binding protein, DeltaIGF-I% correlated with weight gain (r = 0.41). There was no correlation between the IGF-I response and intestinal permeability as assessed by urinary lactulose/rhamnose excretion. Treatment failures (group B) included more children with clinical (relative risk, 4.8; 95% confidence interval, 1.2 to 19.7) and culture proven sepsis at admission and higher concentrations of serum CRP (median (range), 36 (0-182) v 10 (0-240) mg/l) at admission. There was a negative correlation between admission CRP concentration and DeltaIGF-I% (r = -0.45). CONCLUSIONS: In comparison with serum albumin, prealbumin, and retinol binding protein, serum IGF-I increment is a better marker of nutritional recovery in malnourished children with persistent diarrhoea. The possible association of systemic infections, serum IGF-I response, and mucosal recovery needs evaluation in future studies.     

The effects of galanin on growth hormone secretion in children of normal and short stature

We have evaluated the effect of galanin (Gal), a newly identified hypothalamic peptide, on growth hormone (GH) secretion in 10 children with normal stature (NS), nine with constitutional growth delay (CGD), and five with isolated GH deficiency (IGHD). Gal was infused intravenously at a rate of 8 or 15 micrograms/kg/h. All children also underwent an acute oral clonidine test (0.15 mg/m2). In CGD children the mean plasma GH peak after 8 micrograms/kg/h of Gal infusion (13.3 +/- 1.7 ng/mL; mean +/- SEM) was higher (p less than 0.02) than in NS children (8.5 +/- 0.8 ng/mL). When the dose of Gal was increased to 15 micrograms/kg/h the mean plasma GH peak in CGD children (18.5 +/- 3.5 ng/mL) was still higher than in the NS group (13.2 +/- 2.9 ng/mL), although not significantly so. In IGHD children the mean plasma GH peak elicited by 8 or 15 micrograms/kg/h of Gal (3.8 +/- 0.7 and 3.9 +/- 0.5 ng/mL, respectively) was lower than that obtained in either CGD (p less than 0.0002) or NS children (p less than 0.001). In NS children the mean plasma GH peak after acute clonidine administration (22.3 +/- 3.0 ng/mL) was higher than that observed after either dose of Gal used (p less than 0.001 and p less than 0.05 with 8 and 15 micrograms/kg/h, respectively). In CGD or IGHD children mean plasma GH peak after acute clonidine (14.8 +/- 2.6 and 4.1 +/- 1.2 ng/mL, respectively) was not significantly different from that observed after either dose of Gal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of urinary growth hormone and IGF-I excretion in small- and appropriate-for-gestational-age infants and healthy children

The output of urinary growth hormone (GH) and IGF-I were quantitated by RIA in 12-h urine collections obtained from infants who were preterm, small for gestational age (PT-SGA, n = 13); preterm, appropriate for gestational age (PT-AGA, n = 27); full term, small for gestational age (FT-SGA, n = 13); and full term, appropriate for gestational age (FT-AGA, n = 29); and from normal children (n = 33). The amounts of GH and IGF-I (mean +/- SEM) excreted by the PT-SGA and FT-SGA infants were not significantly lower than those excreted by the PT-AGA and FT-AGA groups, respectively [GH (micrograms/kg): PT-SGA 13.7 +/- 3.1 versus PT-AGA 14.0 +/- 2.2, FT-SGA 7.8 +/- 2.4 versus FT-AGA 6.6 +/- 1.8; IGF-I (nmol/kg): PT-SGA 0.52 +/- 0.09 versus PT-AGA 0.53 +/- 0.04, FT-SGA 0.31 +/- 0.05 versus FT-AGA 0.35 +/- 0.04]. All infant groups exhibited significantly greater outputs of urinary GH and IGF-I compared with the children (p less than 0.01). The plasma concentrations of GH in all infant groups were high, whereas the plasma IGF-I levels were low. Microalbumin and beta-2 microglobulin excretion did not correlate with urinary GH and IGF-I output. Despite the higher microalbumin output in FT babies, urinary GH and IGF-I excretion was lower in these groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

The impact of the human immunodeficiency virus type 1 on the management of severe malnutrition in Malawi

A study was undertaken in a central nutritional rehabilitation unit in southern Malawi to assess the impact of HIV infection on clinical presentation and case fatality rate. HIV seroprevalence in 250 severely malnourished children over 1 year of age was 34.4% and overall mortality was 28%. HIV infection was associated significantly more frequently with marasmus (62.2%) than with kwashiorkor (21.7%) (p < 0.0001). Breastfed children presenting with severe malnutrition were significantly more likely to be HIV-seropositive (p < 0.001). Clinical and radiological features were generally not helpful in distinguishing HIV-seropositive from HIV-seronegative children. The case fatality rate was significantly higher for HIV-seropositive children (RR 1.6 [95% CI 1.14-2.24]). The increasing difficulties of managing the growing impact of HIV infection on severely malnourished children in Malawi are discussed in the context of reduced support for nutritional rehabilitation units.