Diagnosis Of Gh Deficiency Classical Evaluation

Diagnosing GHD is not a simple process, but involves multiple laboratory and clinical criteria. Since the late 1950s, when it was first recognized that GH isolated from human pituitaries would stimulate growth in children with deficient GH secretion, clinicians and clinical scientists have been exploring ways of defining which children would benefit from available GH therapy. The introduction of expensive, commercial, recombinant DNA-derived hGH has only intensified the need to perfect diagnostic tools.

Current practice incorporates a combination of clinical, auxologic, and laboratory criteria to define GHD. This begins with an evaluation of stature, relative to genetic expectations, and growth velocity, calculated from serial height determinations. Children who demonstrate consistently subnormal growth velocities for age are candidates for further screening. This generally begins with exclusion of non-GHAD causes of poor growth and incorporates a thorough history, physical examination, bone age assessment, and laboratory screening as appropriate. The majority of children referred to endocrine clinics for short stature will not have GHD. It is important to separate those children with normal variants of growth, such as constitutional delay of growth or puberty, or intrinsic short stature from those with chronic diseases that may be clinically silent except for their effects on growth.

Laboratory assessment of GH sufficiency is difficult because of the intermittent, pulsatile pattern of GH secretion. Single GH levels cannot predict overall GH pulse amplitude, a value that correlates with GH adequacy. The gold standard for diagnosis of GHD involves the administration of pharmacologic stimuli of GH followed by serial blood sampling. Choosing whom to test should be based primarily on objective criteria. Children who have documented subnormal bone age-adjusted growth velocities, severe delays in skeletal maturation, or obvious predispositions to pituitary dysfunction (including intracranial tumors or other pituitary hormone deficiencies) are deserving of further laboratory evaluations. IGF-1, IGFBP-3, and GHBP levels are commercially available and can be useful adjuncts in diagnosing GHD. However, these tests are also problematic since some children with GHD may have values in the normal range (142-144). Similarly, some children with malnutrition or liver disease may have low levels of these growth factors.

In most pediatric endocrine centers, provocative testing procedures for GH adequacy incorporate two of the following GH stimuli: l-dopa, clonidine, arginine, propranolol, glucagon, insulin induced hypoglycemia, and/or exercise. An inadequate response (currently defined in most centers as peak GH levels of <10 ng/mL) suggests GHD. Unfortunately, even provocative GH testing is not a reliable gold standard: age and sex-specific norms are inadequately determined, GH assays in use are not well-standardized, and the specificity and result reproducibility of GH tests are poor (145). A consensus statement published by 16 endocrinologists at 14 centers in 1994 concluded that careful auxological evaluation, supplemented by assessment of appropriate elements of the GH-IGF axis, provides the best foundation for a rational diagnosis of GHD (146).

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