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Is the isolated Idiopathic growth hormone deficiency a simply diagnostic consensus construct?.
- Jairo Echeverry-Raad, Patricia Agualimpia (14 July 2002)
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Diagnosis of Growth Hormone Deficiency
- Sandro Loche, Mohamad maghnie, Marco Cappa (23 August 2002)
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Jairo Echeverry-Raad, Associated Professor Universidad Nacional de Colombia, Bogotá, Colombia, South América, Patricia Agualimpia
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We have reviewing the Jean-Claude Carel´s, et al, elegant paper “Adult height after long term treatment with recombinant growth hormone for idiopathic isolated growth hormone deficiency: observational follow up study of the French population based registry, published in BMJ 2002;325,july 13. We would like to ask some questions and some comments in this respect: 1. Was Growth Hormone administration, in those individuals with Idiopathic growth hormone deficiency, given with the only object to gain height in the adulthood, more than expected by natural history?. If answer is affirmative, is it cost effectiveness for a society to invest approximate US $20.000.oo for each won centimetre (4.2 cm /3.2 years of treatment)?. 2. Does the isolated Idiopathic growth hormone deficiency associate other metabolic alterations and risks (vr. gr. cardiovascular disease) in the adulthood that, the exogenous administration of hormone must be permanent, to permit to reduce these risk?. In other words, is the isolated Idiopathic growth hormone deficiency a disease, a illness, a disorder, a risk factor, or a simply diagnostic consensus “construct”?. 3. Unfortunately the study evidence the same bias and difficulties inherent to the design, that others observational studies that try to evaluate the impact of some intervention by means of non-randomised assignment trials. As you will surely know, the estimates by means of not- experimental designs, tends to be overestimated, even more after multiple comparisons, despite to reduce the significance level to reject the null hypothesis. We remark the sufficient follow-up of yours patients, although with important losses, and to have established an adequate variables outcome, like the adulthood height obtained (a cut-off done before the four years follow-up would of shown a wrong clinical and statistical difference in that moment – fig 2-). But what could the patients appreciate about their quality of life during the treatment regarding the results and costs produced? 4. Could the authors undergoing an additional exploratory analysis of subgroups compare, those patients with isolated Idiopathic growth hormone deficiency that, for some reason, did not received growth hormone, with those that completed the treatment and those that finished prematurely? This could be help to understanding the natural history of “isolated Idiopathic growth hormone deficiency”. Jairo Echeverry-Raad MD, Patricia Agualimpia-Franky M.D Paediatricians Department of Pediatrics Universidad Nacional de Colombia Bogotá, Colombia, South América. . |
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Sandro Loche, Pediatric Endocrinologist Ospedale regionale per le Microcitemie, 09121 Cagliari, Italy, Mohamad maghnie, Marco Cappa
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Dear Sirs, we read with great interest the paper by Dr. Carel et al. (1) and the editorial by Dr. Saenger (2) published in the 13 july issue of the journal. We do agree with Dr. Carel that many children treated for idiopathic growth hormone deficiency (GHD) do not have this condition. In fact, we and others have shown that the great majority of children with idiopathic growth hormone deficiency show normalization of their growth hormone response to stimulation tests when retested at the attainment of final height (3-7). In our study (7), we found that only GHD patients with anatomical abnormalities of the hypothalamic pituitary area at MRI had permanent GHD, while all the others had normal GH secretion at re- testing. Furthermore we have recently shown that among 33 prepubertal children with a biochemical diagnosis of GHD (i.e. a GH response to two stimulation tests <10 µ/L), 28 had a normal response when retested after 2-6 months (8). “Normalisation” of the GH response to stimulation occurred irrespective of the time interval from the first evaluation, and could not be explained by the effect of puberty, since none of our patients had entered puberty before re-evaluation, a finding which would not support the concept of a transient GH secretory defect that would subside under the effects of the pubertal secretion of sex steroids. We and others have shown that in patients with severe, unequivocal GHD, IGF-I and IGFBP-3 concentrations are invariably reduced (8, 9). This indicates that subnormal concentrations of IGF-I and IGFBP-3 can be considered diagnostic of GHD, provided other causes of reduced IGF- I/IGFBP-3 such as malnutrition, hypothyroidism, renal failure or diabetes are excluded. This observation, coupled with the fact that IGF-I concentrations do not correlate with the results of GH stimulation tests (8) suggests inadequacy of our assessment of GH secretion, and stress the need for careful evaluation of the short child and eventual revision of the current diagnostic criteria. Although biochemical tests for GH secretion clearly distinguish children with severe GHD of pituitary origin, recognition of more subtle forms of GH insufficiency still represents a diagnostic dilemma. Thus, a diagnosis of idiopathic GHD cannot be based solely on the results of the stimulation tests but requires evaluation of multiple biochemical and clinical/auxological parameters. We are convinced that patients with pathological GH responses to provocative tests but normal MRI findings of the hypothalamic-pituitary area should be re-evaluated and followed-up before a diagnosis of GHD is firmly established. References 1. Carel JC, Ecosse E, Nicolino M, Tauber M, Leger J, Cabrol S, Bastié-Sigeac I, Chaussain JL, Coste J. Adult height after long term treatment with recombinant growth hormone for idiopathic growth hormone deficiency: observational follow-up of the French population based registry. BMJ 2002; 325:70-76 2. Saenger P. Growth hormone in growth hormone deficiency. BMJ 2002; 325:58-9 3. Cacciari E, Tassoni P, Cicognani A Pirazzoli P, Salardi S, Balsamo A, Cassio A, Zucchini S, Colli C, Tassinari D, Tani G, Gualandi S. Value and limits of pharmacological and physiological tests to diagnose growth hormone (GH) deficiency and predict therapy response: first and second retesting during replacement therapy of patients defined as GH deficient. J Clin Endocrinol Metab 1994; 79: 1663-69. 4. Longobardi S, Merola B, Pivonello R, Di Rella F, Di Somma C, Colao A, Ghigo E, Camanni F, Lombardi G. Reevaluation of growth hormone (GH) secretion in 69 adults diagnosed as GH-deficient patients during childhood. J Clin Endocrinol Metab 1996; 81:1244 –7. 5. Tauber M, Moulin P, Pienkowski C, Journet B, Rochiccioli P. Growth hormone (GH) retesting and auxological data in 131 GH-deficient patients after completation of treatment. J Clin Endocrinol Metab 1997; 82: 352-6. 6. Juul A, Kastrup KW, Pedersen SA, Skakkebaek NE. Growth hormone (GH) provocative retesting of 108 young adults with childhood-onset GH deficiency and the diagnostic value of insulin-like growth factor I (IGF- I) and IGF-binding protein-3. J Clin Endocrinol Metab 1997; 82:1195-201 7. Maghnie M, Strigazzi C, Tinelli C, Autelli M, Cisternino M, Loche S, Severi F. Growth hormone deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults. J Clin Endocrinol Metab 1999; 84:1324-8 8. Loche S, Bizzarri C, Maghnie M, Faedda A, Tzialla C, Autelli M, Casini MR, Cappa M. Results of early re-evaluation of growth hormone (GH) secretion in short children with apparent gh deficiency. J Pediatr 2002; 140:445-9 9. Rosenfeld RG, Albertsson-Wikland K, Cassorla F, Frasier SD, Hasegawa Y, Hinz RL, Lafranchi S, Lippe B, Loriaux L, Melmed S, Preece MA, Ranke MB, Reiter EO, Rogol AD, Underwood LE, Werther GA. Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab 1995; 80:1532–40 Sandro Loche
Mohamad Maghnie
Marco Cappa
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