Kamilia Laarej

Serum IGF-I and IGFBP-3 Reference Values from a Chemiluminescent Assay in Normal Children and Adolescents of Hispanic and Italian Origin: Presence of Sexual Dimorphism in IGF-I Values

Serum IGF-I and IGFBP-3 assays are used to monitor rhGH treatment. Some discrepancies in results obtained by means of different assays have been reported. The aim of this study was to establish normal ranges for circulating IGF-I and IGFBP-3 in children and adolescents of Hispanic and Italian origin. Circulating levels of IGF-I and IGFBP-3 were measured in 169 Hispanic and Italian prepubertal children and 66 adolescents of both sexes, using a chemiluminescent assay. Serum levels of IGF-I and IGFBP-3 increased from early childhood into adolescence. After pubertal peaks of IGF-I and IGFBP-3, slight decreases were observed with increasing age. Furthermore, serum IGF-I levels were significantly higher in girls than in boys, suggesting a sexual dimorphism in serum IGF-I values in late prepuberty and early puberty. Differences in IGF-I and IGFBP-3 absolute values between our study and previous studies suggest the need to establish reference ranges for each ethnic group.

Common adipokine features of neonates and centenarians

Abstract Adipose tissue seems to be a pivotal organ in the aging process. We investigated whether healthy aging could have its roots in a sound metabolic condition from the first year of life by evaluating leptin and adiponectin levels in neonates [33 adequate for gestational age (AGA) and 29 small for gestational age (SGA)], 48 centenarians, and 50 healthy elderly subjects. At birth, SGA neonates showed lower leptin levels (SGA 0.88±0.28; AGA 2.22±0.91 ng/mL; p<0.05) and comparable adiponectin levels with respect to AGA. At 1 year, SGA showed increased leptin (SGA 1.74±0.28; AGA 1.31±0.19 ng/mL) and slightly reduced adiponectin concentrations (SGA 35.51±2.53; AGA 38.56±3.18 μg/mL) than AGA. Centenarians showed lower leptin (centenarians 18.71±3.78; elderly 34.81±7.27 ng/mL; p<0.05) and higher adiponectin levels (centenarians 55.63±7.7; elderly 33.51±4.1 μg/mL; p<0.05) than elderly subjects. Centenarians, like AGA infants during the first year of life, show a favorable adipokine profile, suggesting that the metabolic condition at early age could affect the longevity of an individual.

Effect of human recombinant growth hormone therapy on circulating levels of erythropoietin and granulocyte-colony stimulating factor in short children.

Several reports suggest a role of growth hormone (GH) in the regulation of the haematopoietic system, as regards the normal differentiation and function of blood cells. The aim of this study was to evaluate the influence of rhGH therapy on erythropoietin (Epo) and granulocyte-colony stimulating factor (G-CSF) levels in 18 prepubertal short children with idiopathic GH deficiency (GHD) (n = 8) or without GHD (n = 10), during the first year of treatment. In non-GHD children Epo levels significantly decreased and G-CSF levels increased from basal to 12 months of therapy, whereas in GHD children they did not change significantly. Circulating levels of G-CSF are significantly lower in GHD than in non-GHD children. In non-GHD children the number of red blood cells, haemoglobin and haematocrit values significantly increased after 1 year of rhGH treatment. rhGH therapy influences Epo and G-CSF levels in short non-GHD children, while it shows no effects in GHD children.

Diagnosis of growth hormone deficiency is affected by calibrators used in GH immunoassays.

Growth hormone (GH) values vary among immunoassays depending on different factors, such as the assay method used, specificity of antibodies, matrix difference between standards and samples, and interference with endogenous GH binding proteins (GHBPs). We evaluated whether the use of different calibrators for GH measurement may affect GH values and, consequently, the formulation of GH deficiency (GHD) diagnosis in children. Twenty-three short children (5 F, 18 M; age 11.4±3.1 years), with the clinical characteristics of GHD (height:  -2.3±0.5 SDS; height velocity  -2.3±1.5 SDS; IGF-I  -1.2±0.9 SDS), underwent GH stimulation tests to confirm the clinical diagnosis of GHD. Serum GH values were measured with Immulite 2000, using 2 different calibrators, IS 98/574, a recombinant 22 kDa molecule of more than 95% purity, and IS 80/505, of pituitary origin and resembling a variety of GH isoforms. We found blunted GH secretion in 20 subjects with the Immulite assay using the IS 98/574 GH as a calibrator, confirming the diagnosis of GHD. Subsequently, using IS 80/505 GH as a calibrator, in the same samples only 14 children showed reduced GH levels. The total cost for the first year of GH therapy of patients diagnosed with IS 98/574 as a calibrator was higher than that for patients diagnosed with IS 80/505 as a calibrator. These data confirm that GH values may depend on different calibrators used in the GH assay, affecting the formulation of GHD diagnosis and the consequent decision to start GH treatment.

Changes in growth hormone receptor gene expression during therapy in children with juvenile idiopathic arthritis

Background: High levels of cytokines in juvenile idiopathic arthritis (JIA) can alter target cell sensitivity to growth hormone (GH) leading to short stature in adulthood. We hypothesized that the down-regulation of GH receptor (GHR) gene expression could be involved in growth failure of children with JIA. Methods: In 18 (12 F and 6 M) prepubertal JIA patients and 13 age- and sex-matched healthy children, we evaluated serum growth-promoting factors and inflammatory indexes. We also measured GHR gene expression, by real-time PCR, in lymphocytes of patients and controls. All parameters were evaluated in patients before and after treatment of JIA. Results: The most interesting (p = 0.007) result was the increase in GHR mRNA expression in all JIA patients. Moreover, we observed a significant (p = 0.0156) decrease in IL-6 levels in JIA patients after 2 years of therapy (19.37 ± 41.01) with respect to basal values (90.84 ± 124.71). On the contrary, IGF-I significantly (p = 0.0005) increased to a mean SDS value of 0 (range -1.69 to +1.70 SDS) with respect to values at disease onset (-0.64 SDS). Conclusions: Our preliminary data suggest that the restoration of both GHR gene expression and IGF-I secretion correlate with inactive disease in JIA children.

Efficacy of long-term growth hormone therapy in short children with reduced growth hormone biological activity.

Aim: The optimal GH regimen, in terms of cost-effectiveness, in children with normal GH immunoreactivity but reduced bioactivity is still debated. Methods: In 12 GH-deficient (GHD) and 12 bioinactive GH children undergoing GH treatment we evaluated the increase in growth velocity, the difference between target height and final stature and the incremental cost-effectiveness ratio. Results: We found a significant (p<0.05) increase in growth velocity in both groups during the first year of GH treatment (non-GHD: from −1.7 to 5.4 SDS; GHD: from −1.46 to 4.74 SDS). There was no statistically significant variation between the two groups in the difference between final height and target height. We did not find any significant difference in cost/height gain between GHD (1925.28±653.15 euro) and bioinactive GH children (1639.55±631.44 euro). There were also no significant differences in cost/year of therapy between GHD (12347.68±2018.1 euro) and bioinactive GH children (11355.08±1747.61 euro). Conclusion: In children with reduced GH biological activity, confirmed by the increase of serum IGF-I levels during generation test, the cost of GH treatment is justified by the positive results obtained in growth and adult height as in classical GHD patients.

Is BaF3 bioassay useful to identify patients with bioinactive growth hormone

ABSTRACT We analyzed the ability of the BaF3 cell line bioassay to select patients with biologically inactive GH. We first evaluated the biological response of the Ba/F3-hGHR cells to rhGH additional doses from 10 to 5000 pg/ml. The concentration points corresponding to the linear part of the curve were selected. We then analyzed a group of sera, diluted like the standard, including the entire range of GH concentrations that can be analyzed by bioassay. The serum/standard area below the curve ratio was calculated. Serum GH immunoactivity determined by IMMULITE/GH bioactivity ratios was calculated. Our experimental data showed that GH-bioactivity/GH-immunoactivity ratios below 0.303 are indicative of a bioinactive GH molecule. This bioassay would recognize only extreme cases of GH bioinactivity, and it would not be a useful tool in the search for patients with altered forms of GH.

Hyperimmunoglobulinaemia in Babinga Pygmies is present from infancy

Pygmies, a population characterized by short stature, have high immunoglobulin (Ig) concentrations. In this study, we evaluated Ig levels in Cameroons Babinga Pygmies from infancy to adulthood and the effects of a national health program on these Ig levels. We found that IgG and IgM levels were outside the normal range for Italians of the same age and were comparable to those measured in Babinga Pygmies living in the same region by Siccardi in 1975. In conclusion, the hypergammaglobulinaemia of Babinga Pygmies is already present in infants and is not affected by sanitation improvements, suggesting that it could be partly genetically-determined.

La diagnosi di deficit di ormone della crescita può dipendere dalle metodiche di laboratorio utilizzate

Obiettivo: i valori di ormone della crescita variano notevolmente in dipendenza dalle principali metodiche di dosaggio, dagli anticorpi utilizzati, dal tipo di calibratore e dall’interferenza con la proteina legante il GH. Abbiamo valutato se l’uso di differenti calibratori per la misurazione del GH con il metodo Immulite possa modificare i valori del GH ottenuti e, di conseguenza, la diagnosi di deficit di GH (GHD) nei bambini. Disegno dello studio: 18 bambini di bassa statura (4 femmine e 14 maschi; eta 11.4±3.1 anni), con le caratteristiche cliniche di soggetti con GHD (altezza: -2.1±0.6 SDS; velocita di crescita: -2.3±1.5 SDS; IGF-I: -1.2±0.9 SDS), sono stati arruolati nello studio e sottoposti ai test di stimolo per la secrezione di GH per con-fermare la diagnosi di GHD. Metodi: il GH e l’IGF-I sierico sono stati misurati con un metodo immunometrico chemiluminescente completamente automatico, l’Immulite 2000. Risultati: la valutazione della secrezione di GH con il saggio Immulite, usando il GH umano ricombinante 98/574 come calibratore, ha rilevato una insufficiente secrezione di ormone della crescita in 15 su 18 soggetti, confermando la diagnosi clinica di GHD. Successivamente abbiamo misurato i livelli di GH negli stessi campioni usando come calibratore il GH derivato dall’ipofisi IS 80/505, trovando il deficit di GH solo in 11 soggetti. Conclusioni: questi dati confermano che il valore di GH rilevato dipende dai differenti calibratori utilizzati e che questi sono quindi determinanti per la diagnosi di deficit di GH e quindi per la decisione di intraprendere una terapia sostitutiva.

Andamento dei livelli di leptina e adiponectina nel corso della vita

Il tessuto adiposo sembra essere un organo di fondamentale importanza nel processo di invecchiamento. Abbiamo studiato come l’invecchiamento in buone condizioni di salute possa avere radici nel profilo metabolico del primo anno di vita, valutando i livelli di leptina e adiponectina in eta neonatale (15 AGA e 11 SGA), in 30 centenari e in 31 soggetti anziani sani. Alla nascita, i neonati SGA (Small for Gestational Age) mostrano piu bassi livelli di leptina rispetto ai neonati AGA (Adeguate for Gestational Age) (SGA 0.86±0.36, AGA 1.49±0.60 ng/ml; p<0.05) e livelli comparabili di adiponectina. Ad un anno, gli SGA mostrano un aumento nei valori di leptina (SGA 1.86±0.35, AGA 1.24±0.16 ng/ml) e una lieve riduzione di quelli dell’adiponectina (SGA 37.17±2.30, AGA 36.90±2.20 μg/ml) rispetto ai soggetti nati AGA. I centenari presentano livelli di leptina ridotti rispetto ad un gruppo di anziani (centenari 18.33±4.00, anziani 39.97±11.10 ng/ml; p<0.05), ma valori di adiponectina maggiori (centenari 60.93±10.80, anziani 36.35±5.68 μg/ml; p<0.05). I centenari, similmente ai bambini AGA durante il primo anno di vita, mostrano un profilo adipochinico favore-vole; cio suggerisce che la condizione metabolica in eta infantile potrebbe influenzare la longevita.