CEDIE   05498
CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
A Critical View of Laboratorial Diagnosis of Growth Hormone Deficiency
Autor/es:
HORACIO DOMENÉ
Lugar:
San Pablo, Brasil
Reunión:
Congreso; 8vo Congreso Paulista de Endocrinologia e Metabologia; 2009
Institución organizadora:
Sociedade Brasileira de Endocrinologia e Metabologia
Resumen:
A Critical View of Laboratorial Diagnosis of Growth Hormone Deficiency Horacio M. Domené Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños R. Gutiérrez, Buenos Aires, Argentina. The diagnosis of growth hormone deficiency during childhood is still controversial. However, there is consensus that it is a multifaceted process requiring comprehensive clinical and auxological assessment, combined with biochemical evaluation of the GH-IGF axis and radiological assessment. The diagnosis of GHD in a child presenting short stature (defined as a height 2  SDS below the population mean) should not be initiated before other causes of short stature such as hypothyroidism, celiac disease, chronic systemic diseases, and chromosomal abnormalities have been excluded. The biochemical diagnosis of GHD has traditionally been based on provocative tests using a variety of GH stimulation agents. Nevertheless, the criteria to define a cut-off level to exclude the GHD diagnosis have relied more on arbitrarily defined GH levels than on normative data. In addition, these tests have also been criticized because they are non-physiological, the GH responses are non-reproducible, depending on: a) pubertal development, b) the use of sex steroid priming and c) the assay used for GH measurement. The majority of these criticisms have been resolved by performing at least two well standardized tests (insulin, arginine or clonidine), selecting a cut-off limit based upon a defined GH assay, with low intra- and inter-assay variability and with the use of sex steroid priming, particularly in the immediate peribubertal period, when low GH levels frequently occur. In these conditions the tests have appropriate specificity for the diagnosis of GHD. When isolated GHD is suspected, two GH provocative tests are required, while in those subjects with defined central nervous system defects, multiple pituitary hormone deficiency, or with genetic defects, one GH test will suffice. Even though spontaneous GH secretion is more reproducible than stimulation tests, it has a lower sensitivity, especially in prepubertal children, and it does not represent an advantage over provocative tests. A second line of action for the diagnosis of GHD is the use of biochemical markers of GH action such as IGF-I and IGFBP-3. Some advantages of this approach are that it only requires a blood sample, these markers are relatively stable in the circulation, and they correlate with endogenous GH secretion. However, IGF-I and/or IGFBP-3 within normal limits have been reported in GHD children present and more importantly, a consistent percentage of children with idiopathic short stature (ISS) have low levels of these markers.  By expressing IGF-I and IGFBP-3 levels in SDS using normal reference data adjusted according to age and pubertal development together with an accurate selection of threshold values to discriminate between GHD and ISS by ROC curves the diagnostic efficiency of these markers can be improved. Moreover, since the variability observed in these markers are related to the presence of polymorphisms  in the genes encoding these proteins, we have shown that by obtaining genotype specific cut-off values for IGFBP-3 levels considering the -202 A/C polymorphism, the specificity and diagnostic efficiency of IGFBP-3 measurements are improved, even above that of IGF-I measurement and with similar diagnostic efficiency to ALS (acid labile subunit) measurement but with a slightly higher sensitivity. Finally, an additional advantage to investigate simultaneously GH secretion by provocative tests and IGF-I and IGFBP-3 levels is the possibility of identifying  patients presenting GH insensitivity with a normal or elevated GH response  associated to low levels of IGF-I or IGFBP-3. Recent findings of genetic defects along the GH-IGF axis indicate that these alterations should be investigated in these children.