Anthropometric, biochemical and clinical assessment of malnutrition among Egyptian children with chronic liver diseases: a single institutional cross-sectional study.

BACKGROUND: Malnutrition is a common problem among children with chronic liver diseases (CLD). We aimed to assess the nutritional status of children with CLD and to correlate the anthropometric indices with the severity of liver disease, liver function tests, insulin growth factor-1 (IGF-1) and 25-hydroxy vitamin D (25- OH D). METHODS: A total of 69 patients with CLD and 50 healthy controls (6 months - 6 years) were included in the study. Nutritional status was assessed by anthropometric indices expressed in standard deviation score (Z score), biochemical, hematological and clinical parameters. RESULTS: We found 52.2% of CLD patients underweight by weight for age (W/A); 50.2% were stunted by height for age/ length for age (HAZ or LAZ); and 39% exhibited wasting by weight/height or (length) for age (W/HZ or W/LZ) z scores analysis. The mean values of z scores for all anthropometric parameters were significantly correlated with unconjugated and conjugated bilirubin and INR (p < 0.05), except HAZ or LAZ. Also, a significant correlation to albumin was found, except for W/HZ or (W/LZ) (p = 0.157). The z scores < - 2 SD based on W/ H versus arm indicators showed significant differences in MUAC, UAA and AMA (p < 0.001). We found no correlation between anthropometric z-scores and the mean IGF-1 and (25- OH D) values (p > 0.05). Malnutrition was directly correlated with the severity of hepatic dysfunction, particularly, Child-Pugh C cases. The mean IGF-1 and (25- OH D) values were significantly correlated with the severity of liver disease (p < 0.001). CONCLUSIONS: Our results identified anthropometric arm indicators and MUAC/A measurements as an effective applied methods for assessing nutritional status in CLD children. Moreover, Integrating comprehensive clinical assessment, anthropometric measurements and objective biochemical analyses is essential for evaluation, follow-up and management of CLD children with variable degree of malnutrition.

Metabolic and immunological assessment of small-for-gestational-age children during one-year treatment with growth hormone: the clinical impact of apolipoproteins.

Children born small for gestational age (SGA) are at a higher risk for metabolic disorders later in life. In this study, we aimed to characterize young SGA children without catch-up growth and evaluate the effects of GH treatment on endocrinological, metabolic, and immunological parameters. Study design is a one-year single hospital-based study included prospective observation of SGA patients during 12 months of GH treatment. Clinical and laboratory profiles of SGA children at baseline were compared with controls born appropriate size for age. Twenty-six SGA children (median age, 3.4 years) and 26 control children (median age, 3.8 years) were enrolled. Anthropometric, hematologic, biochemical, immunological, and endocrinological parameters were assessed at baseline and 1, 3, 6, 9, and 12 months after the start of GH treatment. As a result, median height SD score (SDS) of SGA children increased by +0.42 with 12-month GH treatment. Body mass index SDS was lower in SGA children than in controls. Serum apolipoprotein A1 increased, whereas apolipoprotein B decreased during GH treatment. Serum leptin and resistin levels, which were lower in SGA children than in controls at baseline, did not change remarkably with GH treatment. Monocyte counts, which were lower in SGA patients at baseline, increased after GH treatment. Neutrophil counts significantly increased after GH treatment. Natural killer cell ratios, which were higher in SGA patients, decreased after GH treatment. In conclusion, there was no evidence suggesting metabolic abnormalities in SGA children. Serum apolipoprotein changes might predict the beneficial role of GH treatment in lowering cardiometabolic risk.

Eggs early in complementary feeding increase choline pathway biomarkers and DHA: a randomized controlled trial in Ecuador.

Background: Choline status has been associated with stunting among young children. Findings from this study showed that an egg intervention improved linear growth by a length-for-age z score of 0.63.Objective: We aimed to test the efficacy of eggs introduced early in complementary feeding on plasma concentrations of biomarkers in choline pathways, vitamins B-12 and A, and essential fatty acids.Design: A randomized controlled trial, the Lulun ("egg" in Kichwa) Project, was conducted in a rural indigenous population of Ecuador. Infants aged 6-9 mo were randomly assigned to treatment (1 egg/d for 6 mo; n = 80) and control (no intervention; n = 83) groups. Socioeconomic data, anthropometric measures, and blood samples were collected at baseline and endline. Household visits were made weekly for morbidity surveillance. We tested vitamin B-12 plasma concentrations by using chemiluminescent competitive immunoassay and plasma concentrations of choline, betaine, dimethylglycine, retinol, essential fatty acids, methionine, dimethylamine (DMA), trimethylamine, and trimethylamine-N-oxide (TMAO) with the use of liquid chromatography-tandem mass spectrometry.Results: Socioeconomic factors and biomarker concentrations were comparable at baseline. Of infants, 11.4% were vitamin B-12 deficient and 31.7% marginally deficient at baseline. In adjusted generalized linear regression modeling, the egg intervention increased plasma concentrations compared with control by the following effect sizes: choline, 0.35 (95% CI: 0.12, 0.57); betaine, 0.29 (95% CI: 0.01, 0.58); methionine, 0.31 (95% CI: 0.03, 0.60); docosahexaenoic acid, 0.43 (95% CI: 0.13, 0.73); DMA, 0.37 (95% CI: 0.37, 0.69); and TMAO, 0.33 (95% CI: 0.08, 0.58). No significant group differences were found for vitamin B-12, retinol, linoleic acid (LA), α-linolenic acid (ALA), or ratios of betaine to choline and LA to ALA.Conclusion: The findings supported our hypothesis that early introduction of eggs significantly improved choline and other markers in its methyl group metabolism pathway. This trial was registered at clinicaltrials.gov as NCT02446873.

Pituitary Stalk Interruption Syndrome from Infancy to Adulthood: Clinical, Hormonal, and Radiological Assessment According to the Initial Presentation.

BACKGROUND: Patients with pituitary stalk interruption syndrome (PSIS) are initially referred for hypoglycemia during the neonatal period or growth retardation during childhood. PSIS is either isolated (nonsyndromic) or associated with extra-pituitary malformations (syndromic). OBJECTIVE: To compare baseline characteristics and long-term evolution in patients with PSIS according to the initial presentation. STUDY DESIGN: Sixty-seven patients with PSIS were included. Data from subgroups were compared: neonates (n = 10) versus growth retardation patients (n = 47), and syndromic (n = 32) versus nonsyndromic patients (n = 35). RESULTS: Neonates displayed a more severe hormonal and radiological phenotype than children referred for growth retardation, with a higher incidence of multiple hormonal deficiencies (100% versus 34%; P = 0.0005) and a nonvisible anterior pituitary lobe (33% versus 2%; P = 0.0017). Regular follow-up of growth might have allowed earlier diagnosis in the children with growth retardation, as decreased growth velocity and growth retardation were present respectively 3 and 2 years before referral. We documented a progressive worsening of endocrine impairment throughout childhood in these patients. Presence of extra-pituitary malformations (found in 48%) was not associated with more severe hormonal and radiological characteristics. Growth under GH treatment was similar in the patient groups and did not vary according to the pituitary MRI findings. CONCLUSIONS: PSIS diagnosed in the neonatal period has a particularly severe hormonal and radiological phenotype. The progressive worsening of endocrine impairment throughout childhood justifies periodic follow-up to check for additional hormonal deficiencies.

Understanding the complex determinants of height and adiposity in disadvantaged daycare preschoolers in Salvador, NE Brazil through structural equation modelling.

BACKGROUND: Earlier we reported on growth and adiposity in a cross-sectional study of disadvantaged Brazilian preschoolers. Here we extend the work on these children, using structural equation modelling (SEM) to gather information on the complex relationships between the variables influencing height and adiposity. We hope this information will help improve the design and effectiveness of future interventions for preschoolers. METHODS: In 376 preschoolers aged 3-6 years attending seven philanthropic daycares in Salvador, we used SEM to examine direct and indirect relationships among biological (sex, ethnicity, birth order, maternal height and weight), socio-economic, micronutrient (haemoglobin, serum selenium and zinc), and environmental (helminths, de-worming) variables on height and adiposity, as reflected by Z-scores for height-for-age (HAZ) and body mass index (BMIZ). RESULTS: Of the children, 11 % had HAZ < -1, 15 % had WHZ < -1, and 14 % had BMIZ > 1. Of their mothers, 8 % had short stature, and 50 % were overweight or obese. Based on standardized regression coefficients, significant direct effects (p < 0.05) for HAZ were maternal height (0.39), being white (-0.07), having helminth infection (-0.09), and serum zinc (-0.11). For BMIZ, significant direct effects were maternal weight (0.21), extremely low SES (-0.15), and haemoglobin (0.14). Indirect (p < 0.05) effects for HAZ were sex (being male) (-0.02), helminth infection (-0.01), de-worming treatment (0.01), and serum selenium (-0.02), and for BMIZ were extremely low SES (-0.001), helminth infection (-0.004), and serum selenium (0.02). CONCLUSIONS: Of the multiple factors influencing preschoolers' growth, helminth infection was a modifiable risk factor directly and indirectly affecting HAZ and BMIZ, respectively. Hence the WHO de-worming recommendation should include preschoolers living in at-risk environments as well as school-aged children.

Functional and total IGFBP3 for the assessment of disorders of the GH/IGF1 axis in children with chronic kidney disease, GH deficiency, or short stature after SGA status at birth.

OBJECTIVE: IGFBP3 immunoreactivity may appear elevated in patients with chronic kidney disease (CKD), in part due to accumulation of low molecular fragments. The importance of these IGFBP3 variants for binding and inactivation of IGF1 and their relevance for the impaired growth of uremic children are unclear. Nevertheless, IGFBP3, measured as total (t-)IGFBP3, is frequently used as a diagnostic parameter in pediatric CKD patients. A new assay for functional (f-)IGFBP3 exclusively detects IGFBP3 capable of IGF binding. The aim of the study was to evaluate the significance of f-IGFBP3 measurements for the assessment of uremic abnormalities of the GH/IGF1 axis. DESIGN: Prospective cross-sectional study. METHODS: t-IGFBP3, f-IGFBP3, and IGF1 were measured in pediatric CKD patients, including patients with CKD stage 3-4 not on dialysis (CKD, n=33), on dialysis treatment (DT, n=26), patients after renal transplantation (RTx, n=89), healthy children (n=29), children with GH deficiency (GHD, n=42), and small for gestational age (SGA) children (SGA, n=34). RESULTS: Mean t-IGFBP3 SDS was elevated in CKD, DT, and RTx children compared with controls and GHD patients (P≤0.0004). Highest values were reached in DT (P<0.0001 vs all groups). In contrast, mean f-IGFBP3 was similar in all groups (P=0.30). CONCLUSIONS: Pediatric CKD patients displayed elevated serum concentrations of t-IGFBP3 but not f-IGFBP3, supporting the hypothesis that IGFBP3 fragments not binding IGF1 accumulate during uremia. f-IGFBP3 is an indicator of IGFBP3 fragmentation and seems to reflect IGF1 binding in CKD better than t-IGFBP3. However, the role of f-IGFBP3 for the diagnosis of disturbances of the GH/IGF hormonal axis appears to be limited.

Safety of insulin tolerance test for the assessment of growth hormone deficiency in children.

OBJECTIVE: To determine the safety of insulin tolerance test (ITT) for assessing growth hormone (GH) deficiency in children. METHODS: This hospital based study was conducted at the National Institute of Child Health, Karachi from 1st November 2008 till 30th October 2009. All children suspected of growth hormone deficiency, were included after excluding all other causes of short stature. Verbal informed consent was taken from the parents. Children less than 2 years of age, weighing less than 10 kg, untreated/inadequately treated hypothyroidism or Addison's disease, epilepsy, having history of hypoglycaemic fits or cardiac disease were excluded. All children were subjected to the international standard protocol of ITT and their samples of growth hormone and blood sugars were drawn. Complications during the procedure like hypoglycaemia, hypothermia, loss of consciousness, fits, vomiting and failure to achieve hypoglycaemia were recorded. Insulin tolerance test was performed on a total of 168 subjects. The data was entered in SPSS version 17 for analysis. RESULTS: A total of 168 children were subjected to the ITT. Four of them were abandoned as they could not achieve hypoglycaemia despite repeating the dose of insulin. Results were analyzed on 164 children whose mean age was 10 +/- 3.5 years, There were 96 (58%) males and 68 (41%) females. Over all 79.8% children achieved hypoglycaemia. None of the subjects developed any complication (fits, loss of consciousness,) or required intravenous glucose during the test and it was completed in all children with close monitoring. The results showed that there was a significant effect of time after insulin administration on both the blood glucose level (BG) and growth hormone (GH) levels. The blood glucose level decreased rapidly after administration of insulin and was lowest 30 minutes after injection and showed an increasing trend in subsequent readings, becoming almost equal to the baseline value 120 min after injection. From the study group 111 (66%) children were diagnosed as having growth hormone deficiency, 52 (31.3%) were normal and 1 (0.6%) had growth hormone insensitivity. CONCLUSION: ITT in children was found to be a safe and reliable test but can be potentially dangerous and requires very close monitoring and supervision and should be performed in a center with experienced staff.

Usefulness of serum insulin-like growth factor I assessment in the diagnosis of childhood-onset growth hormone deficiency.

The diagnosis of childhood-onset growth hormone (GH) deficiency (GHD) is not straightforward, requiring a comprehensive clinical, anthropometric, biochemical, endocrine, and neuroradiological assessment. Although pharmacological GH stimulation tests are still considered the gold standard for GHD diagnosis, they are burdened by both poor specificity and side effects. The measurement of insulin-like growth factor I (IGF-I), due to its close GH dependency, was proposed for diagnosing GHD. However, a number of factors may affect the measurements. Herein, we propose an algorithm based on both IGF-I determination and anthropometry, aimed at simplifying the diagnosis of GHD in prepubertal children.

Arginine and clonidine stimulation tests for growth hormone deficiency revisited--do we really need so many samples?

Growth hormone (GH) reserve is defined biochemically by the peak serum concentration after stimulation with a known secretagogue. Arginine and clonidine stimulation tests are currently performed with 5 timed blood samples. We evaluated the diagnostic utility of taking fewer samples by retrospectively analyzing 289 tests (202 arginine and 87 clonidine) performed in a single hospital. 123/202 (60.9%) arginine tests and 46/87 (52.9%) clonidine tests had at least one sample above 10 ng/ml. These were defined as negative for GH deficiency and studied further. For arginine tests, three samples taken at 0', 45' and 90' would have provided an acceptable false positive rate of 4.5%. For clonidine tests, two samples taken at 60' and 90' provided a false positive rate of 4.3%. Addition of either a 0' or 120' sample further reduced the false positive rate to 2.2%. Both the arginine and clonidine stimulation tests can be reliably performed with fewer samples.

Decreasing stunting, anemia, and vitamin A deficiency in Peru: results of the Good Start in Life Program.

BACKGROUND: The rates of stunting, iron-deficiency anemia, and vitamin A deficiency in Peru are among the highest in South America. There is little scaled-up experience on how to solve these problems countrywide. OBJECTIVE: To evaluate the Good Start in Life Program during the period from 2000 to 2004. METHODS: Data on weight, height, hemoglobin, serum retinol, urinary iodine, and age were obtained from children under 3 years of age during two transverse surveys in 2000 and 2004. RESULTS: In 2004, the program covered 75,000 children, 35,000 mothers, and 1 million inhabitants from 223 poor communities. The rate of stunting decreased from 54.1% to 36.9%, the rate of iron-deficiency anemia decreased from 76.0% to 52.3%, and the rate of vitamin A deficiency decreased from 30.4% to 5.3% (p < .01). The annual cost per child was US$116.50. CONCLUSIONS: Adaptations of this participative program could contribute to decreased stunting, iron-deficiency anemia, and vitamin A deficiency at the national scale in Peru and many other countries.

Diagnostic efficacy of 0, 30, 45, 60, 90 and 120 min growth hormone samples in insulin tolerance test: utility of growth hormone measurement at different time-points and a cost-effective analysis.

OBJECTIVE: To determine the utility of growth hormone (GH) measurement with the insulin tolerance test (ITT), and to carry out a cost-effective analysis of the diagnosis of GH deficiency. MATERIAL AND METHODS: Ninety-nine patients clinically suspected of GH deficiency were evaluated over a period of 14 months (January 2005 to April 2006). Post-insulin samples of GH and blood glucose (BG) samples were drawn at six different time-points. Serum GH levels of <10 microg/L (prepubertal) and <6.1 microg/L (adolescents) were taken as cut-off for the normal response. RESULTS: Ninety-nine ITTs were carried out during the study period, and GH levels were found to be deficient in 47 subjects. Specificities at different time-points were 0%, 54%, 77%, 62%, 39% and 23% for 0, 30, 45, 60, 90 and 120 min, respectively, in the prepubertal group, and 5%, 41%, 80%, 87%, 77% and 46% at the same time-points for the adolescent group. Accuracy was highest at 45 and 60 min in both the prepubertal and adolescent groups. The receiver operating characteristic curve showed that the highest area under the curve was found in samples drawn at 45, 60 and 90 min in both the prepubertal and adolescent groups. CONCLUSION: Our data suggest that 0, 45, 60 and 90 min samples are sufficient for diagnosing GH deficiency, which could lead to potential cost reductions of up to 29.8%.

Hypopituitary control and complications study (HypoCCS): a decade of an outcomes assessment observational study.

The Hypopituitary Control and Complications Study (HypoCCS) was set up in 1995 to monitor the long-term efficacy of GH replacement therapy in adult patients with GH deficiency (GHD). The key findings to date have focussed on the diagnosis of GHD, the effects of GH on lean body mass, lipids and bone, and the quality of life benefits. Current guidelines recommend that the diagnosis of adult GHD be proven biochemically. However, these tests are not suitable for all patients, and data from this study suggest that the presence of 3 or more pituitary hormone defects can predict adult GHD with 95% accuracy. The 3-yr efficacy analysis showed that GH replacement therapy in adults is effective in improving body composition, bone mass and lipid profiles, but age is an important factor in determining the response to treatment. Quality of life was improved and maintained during long-term GH replacement therapy in adults. Future results will show if these initial benefits have been sustained.

Update on epidemiology, etiology, and diagnosis of adult growth hormone deficiency.

The most updated guidelines for the diagnosis of adult GH deficiency (GHD) come from the GH Research Society Consensus Workshop held in Sydney, Australia, in 2007. Regarding who to test for GHD, advice should be extended from primitive hypothalamic- pituitary diseases and cranial irradiation to include brain injuries (Traumatic Brain Injury in particular). Regarding how to test for GHD, the insulin tolerance test (ITT) remains a provocative test of reference; among classical provocative test, glucagon test has also been validated. Above all, GHRH + arginine and GHRH + GH-secretagogues are now considered, at least, as reliable as ITT for the diagnosis of adult GHD. Interestingly, it is now accepted that very low IGF-I represents definite evidence of severe GHD in congenital forms of GHD and also in patients with acquired multiple hypopituitarism. These patients would skip provocative test; however, as normal IGFI levels do not rule out severe GHD, patients suspected for hypopituitarism showing normal IGF-I levels must undergo a provocative test of GH secretion. Retesting the GH status in the transition age is of major relevance in order to decide about continuing or not recombinant human GH replacement in adult life.

High repeatability of circadian prolactin rhythm assessment results in children.

OBJECTIVES: In normal conditions, prolactin (Prl) secretion manifests a circadian pattern. So far, there have only been but few studies, concerning intrasubject variability and repeatability of the circadian Prl secretion pattern, based on pulse analysis. It seems, that macroscopic analysis based on measurement of Prl concentration at nine time points every 3 hours during 24 hours is an appropriate method to assess Prl profile for clinical purposes. The aim of the study was to assess the repeatability of that circadian Prl secretion pattern in a group of short children without hormonal disorders. MATERIALS AND METHODS: The analysis comprised the results of two circadian Prl profiles, performed from 2 to 14 months in 23 prepubertal children (16 boys) with idiopathic short stature, aged: 10.3+/-2.4 yrs. RESULTS: There were no statistical differences between Prl concentrations at the same time points in the two consecutive profiles, but the comparison of Prl concentrations at 8:00 gave results which were close to the border of statistical significance (p=0.055), what indicated low repeatability of measurement results at that particular time point. There were no statistical differences between the values of particular parameters in macroscopic profile analysis in the first and in the second test. CONCLUSION: Circadian Prl profile, based on nine Prl concentration measurements, taken every 3 hours during one day, is characterized by high repeatability of the results and low intrasubject variability in children, despite the results of Prl concentration at 08:00 o'clock.

Assessment of prolactin secretion in children: a profile of circadian prolactin secretion and the principles for interpreting it.

INTRODUCTION: Prolactin (Prl) is secreted in a circadian pattern, although no method of interpreting it has yet been established. The aim of the study was to assess Prl secretion in children on the basis of the Prl circadian profile and to establish principles for the interpretation of the results obtained by this method. MATERIAL AND METHODS: The analysis comprised 41 healthy short children (25 boys); aged 5.2-16.3 years, in whom hormonal disorders and chronic diseases had been excluded. The children were divided into prepubertal or pubertal subgroups. Serum Prl concentrations were measured every 3 hours for 24 hours. To assess the rhythm the parameters of macroscopic analysis were calculated and receiver operating characteristic (ROC) analysis was performed. The group for comparison consisted of 30 children aged 8.9-17.2 years with hyperprolactinaemia. RESULTS: In each subgroup significantly higher Prl concentrations were observed at night than by day. No statistical differences were noticed between the groups regarding Prl concentrations at particular time points or parameter values during circadian Prl rhythm evaluation. In the group analysed weak correlations were found between age and Prl peak and trough levels. On the basis of ROC analysis criteria for the existence of normal circadian Prl rhythm in children were established. CONCLUSIONS: 1. The presence of normal circadian Prl rhythm is observed if at least one of the following three criteria is fulfilled: amplitude >1.8779; X(n)/X(d) ratio >1.685; regression index <-0.4107. 2. No interpretation in relation to sex, age and stage of puberty is necessary for the circadian prolactin secretion rhythm in children.

Assessment of insulin-like growth factor-I serum concentration as a screening procedure in diagnosing children with short stature.

OBJECTIVES: Insulin-like growth factor-I (IGF-I) secretion is growth hormone (GH) dependent. However the data on using IGF-I assessment as a screening procedure in diagnosing GH deficiency are not consistent. The goal of the study was an analysis of the relations between GH secretion in stimulating tests and plasma IGF-I concentration. PATIENTS & METHODS: The analysis comprised 540 children with short stature in whom two standard GH stimulating tests (GHST) were performed, together with an assessment of plasma IGF-I concentration. The relationships between GH peak in both tests and IGF-I secretion were analysed. RESULTS: There was no correlation either between GH peaks in different tests or between GH and IGF-I secretion in particular patients. Moreover, both the mean IGF-I concentration was similar in the patients with normal and subnormal results of GHST and the mean GH peak in GHST presented similar in the groups of children with normal and decreased IGF-I secretion. CONCLUSIONS: Assessment of IGF-I secretion fails to be a screening procedure for the results of GHST. The lack of correlation between the results of two GHST should be taken into account when evaluating the significance of GHST and IGF-I assessment in diagnosing GH deficiency.

IGF-I and IGFBP-3 assessment in the management of childhood onset growth hormone deficiency.

The diagnosis of growth hormone (GH) deficiency (GHD) in childhood is not straightforward, being still based on a comprehensive clinical, anthropometric, endocrine and neuroradiological assessment. Due to their GH dependency and relative stability in circulation, IGF-I and IGFBP-3 serum concentrations were proposed as reliable indicators of daily GH secretion. However, the sensitivity of assays for both IGF-I and IGFBP-3 is inadequate to exclude the diagnosis of GHD merely on the basis of a normal value of the two parameters, although it seems likely that IGF-I values higher than -1 SD reflect a normal GH secretion. On the other hand, as the specificity of both measurements is over 90%, subnormal concentrations strongly support the diagnosis of GHD. Finally, combining the evaluation of growth velocity with IGF-I measurement, sensitivity and specificity reach a value > or =95%, implying that two subnormal values strongly suggest and two normal values strongly oppose the diagnosis of GHD.

Re-assessment of growth hormone secretion in young adult patients with childhood-onset growth hormone deficiency.

OBJECTIVE: Patients with childhood-onset GH deficiency (coGHD) need retesting in late adolescence or young adulthood to verify whether they need to continue GH treatment. For this purpose the Growth Hormone Research Society (GRS) recommends the insulin tolerance test (ITT), or as an alternative the arginine + growth hormone releasing hormone test (ARG + GHRH test) as a diagnostic tool in adolescents and adults. However, there are no standardized cut-off levels based on normal GH secretion for determining GHD vs. GH sufficiency in young adults for the ITT, the ARG + GHRH test or the pyridostigmine + GHRH (PD + GHRH) test, a further new GH stimulation test. PATIENTS AND MEASUREMENTS: We studied 43 patients (28 with organic coGHD, 15 with idiopathic coGHD; 30 males, 13 females; aged 20.4 years, range 16.2-25.4; body mass index 23.5, range 16.3-35.8) using the ARG [0.5 g/kg intravenously (i.v.)] + GHRH (1 micro g/kg i.v.) test, the PD (120 mg orally) + GHRH (1 micro g/kg i.v.) test and the ITT (0.1 IU/kg i.v.) and compared these data with the results of 40 healthy age- and weight-matched volunteers. RESULTS: The GH response in patients was significantly lower than in healthy controls: ARG + GHRH test, 0.8 micro g/l (interquartile range 0.3-2.6) vs. 51.8 micro g/l (32.6-71.2) in controls (P < 0.0001); PD + GHRH test, 0.9 micro g/l (0.3-1.9) vs. 40.4 micro g/l (27.1-54.4) in controls (P < 0.0001); ITT, 0.1 micro g/l (0.0-0.8) vs. 20.3 micro g/l (14.7-31.7) in controls (P < 0.0001). In the ARG + GHRH test we found a diagnostic sensitivity of 100% and a specificity of 97.5% for a cut-off range from 15.1 to 20.3 micro g/l, in the PD + GHRH test a sensitivity of 100% and a specificity of 97% (cut-off range 9.1-13.1 micro g/l) and in the ITT a sensitivity and specificity of 100% each within a cut-off range from 2.7 to 8.8 micro g/l. CONCLUSION: There were no marked differences in sensitivity and specificity in young adults among ARG + GHRH test, PD + GHRH test and the ITT in assessing GH secretion. Because of the lack of side-effects, the ARG + GHRH test is the recommended method for re-evaluation of coGHD in young adults when pituitary GHD is suspected. Furthermore, in adult patient groups where organic pituitary coGHD is common, the ITT may be completely replaced by the ARG + GHRH test. Because of the predominance of hypothalamic GHD in childhood, the ITT is commonly performed for the re-evaluation of patients with childhood-onset GHD because of its mechanism of GH stimulation. The present results confirm the high discriminatory capability of the ITT in young adults.

Height velocity and IGF-I assessment in the diagnosis of childhood onset GH insufficiency: do we still need a second GH stimulation test?

OBJECTIVE: The diagnosis of GH insufficiency (GHI) in childhood is not straightforward. Our aim was to test the sensitivity and specificity of height velocity (HV), IGF-I, IGFBP-3 and GH stimulation tests alone or in combination in the diagnosis of GHI. DESIGN: A retrospective review of patients with GHI and idiopathic short stature (ISS) diagnosed in our centre and followed up to the completion of linear growth. PATIENTS: Thirty-three GHI children and 56 children with ISS were evaluated. GHI diagnosis was based on fulfilment of anthropometric, endocrine and neuroradiological criteria: stature < or = -2 z-score, delayed bone age (at least 1 year), GH peak response to at least two different provocative tests < 10 micro g/l (20 mU/l), brain MRI positive for hypothalamus-pituitary abnormalities, catch-up growth during the first year of GH replacement therapy > or = 75th centile, peak GH response to a third provocative test after growth completion < 10 micro g/l (20 mU/l). Children with anthropometry resembling that of GHI but with peak GH responses > 10 micro g/l (20 mU/l) were diagnosed as ISS. MEASUREMENTS: All subjects underwent standard anthropometry. GH secretory status was assessed by clonidine, arginine and GHRH plus arginine stimulation tests. IGF-I and IGFBP-3 circulating levels were measured by immunoradiometric assay (IRMA). The following cut-off values were chosen to discriminate between GHI and nonGHI short children: HV < 25th centile over the 6-12 months prior to the initiation of GH therapy, peak GH responses < 10 or < 7 micro g/l (< 20 or < 14 mU/l) and IGF-I and IGFBP-3-values < -1.9 z-score. Sensitivity (true positive ratio) and specificity (true negative ratio) were evaluated. RESULTS: Taking 10 micro g/l (20 mU/l) as the cut-off value, sensitivity was 100% and specificity 57% for GH provocative tests, whereas taking 7 as the cut-off value, sensitivity was 66% and specificity rose to 78%. Sensitivity was 73% for IGF-I and 30% for IGFBP-3 measurement, whilst specificity was 95% for IGF-I and 98% for IGFBP-3 evaluation. HV assessment revealed a sensitivity of 82% and a specificity of 43%. When HV and IGF-I evaluations were used in combination, sensitivity reached 95% and specificity 96%. When both HV and IGF-I are normal (26% of our subjects) GHI may be ruled out, whereas when both the indices are subnormal (23%) GHI is so highly likely that the child may undergo only one GH provocative test and brain MRI and, thereafter, may begin GH therapy without any further test. In case of discrepancy, when IGF-I is normal and HV < 25th centile (44% of children), due to the relatively low sensitivity of IGF-I assessment and low specificity of HV, the patient should undergo GH tests and brain MRI. Finally, in the rare case of HV > 25th centile and subnormal IGF-I-values (7%), due to the high specificity of IGF-I measurement, the child should undergo one provocative test and brain MRI for the high suspicion of GHI. CONCLUSIONS: Our results suggest that a simple assessment of HV and basal IGF-I may exclude or, in association with only one stimulation test, confirm the diagnosis of GH insufficiency in more than half of patients with short stature.