Division of Pediatric Endocrinology Mattel Childrens Hospital at UCLA Los Angeles, California 90095-1752
Address correspondence and requests for reprints to: S. Douglas Frasier, M.D., Emeritus Professor of Pediatrics, Division of Pediatric Endocrinology, Mattel Childrens Hospital at UCLA, 10833 Le Conte Avenue, Los Angeles, California 90095-1752.
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First, are the guidelines, as presented, helpful to the clinician? In addition, what is the overall usefulness of consensus guidelines?
The answer to the first question is clearly positive. However, there are several features, both general and specific, that may limit the application of the GRS recommendations.
The lack of supporting literature, while understandable, greatly lessens the usefulness of the overall presentation.
At the very least, the inclusion of references to various pertinent reviews would have strengthened the recommendations. They would have been less opinion-based and more based on the available evidence. Clearly, the report was written by a committee with an attempt to represent all views. A number of contentious points that have sparked vigorous discussion at scientific meetings over the past 3035 yr are glossed over. Although this makes for a stronger consensus, legitimate competing viewpoints may be lost to the ultimate detriment of patient care.
Throughout the presentation, height and height velocity are expressed as SD and SD score. Whereas this is politically correct and well and good for investigators and for most clinicians, it is not what patients and parents readily understand. The use of height percentiles and growth velocity expressed as cm/yr still deserves a place in the definition of criteria for the evaluation of growth and the response to GH therapy. Reference to normative data, despite its imperfections, would have been helpful.
Several additional specifics are deserving of comment.
Listing the more common chronic systemic illnesses that may lead to growth failure would make it more likely that the laboratory tests that would uncover these conditions would be part of the initial patient evaluation. These would include chronic renal failure, renal tubular acidosis, inflammatory bowel disease, celiac disease, and liver disease.
Because prolonged neonatal jaundice due to deficient conjugation of bilirubin is extremely common and is not a hallmark of GH deficiency, prolonged elevation of direct bilirubin should be specified. Congenital nystagmus is another neonatal physical finding that may indicate GH deficiency and that deserves inclusion.
As stated in the guidelines, the preferable imaging technique to detect underlying intracranial pathology is magnetic resonance imaging. This should be carried out both with and without contrast. Indeed, the guidelines recommend this procedure for all patients shown to have GH deficiency. This approach is far superior to computerized tomography and infinitely superior to plane skill films. The latter should probably be abandoned as simply providing an unnecessary exposure to radiation rather than tolerated as it is in the guidelines.
Listing the other causes of low insulin-like growth factor I, particularly pointing out the effect of malnutrition, would add to the suggested interpretation of low insulin-like growth factor concentrations. Measurement of GH in the presence of neonatal or infantile hypoglycemia should be carried out as part of the so-called "critical sample" analysis. In general, this should be done as an initial step in the evaluation of hypoglycemia rather than after the elimination of metabolic disease from consideration.
These minimal critical comments aside, the section of the guidelines dealing with diagnosis is clear and concise. Of particular usefulness is the stress on considering all of the available information in reaching a conclusion. The appropriate focus is on the patient and not on any particular set of numbers.
The section on treatment of GH deficiency is also, for the most part, clear and is an accurate reflection of current clinical practice. However, I have several critical comments related to therapy as described.
It is recommended that GH be given in the evening on a daily basis. I do not believe that there is sufficient evidence to specify any particular time of day for injections. This places an undue burden on patients and their families. The schedule of injections should be flexible enough to allow each family to adapt it to its activities. Likewise, I am not at all sure that daily injections are preferable to a 6-day a week schedule. The latter gives patients a much-needed day off. Where are the data that unfavorably compares a six times a week with a daily schedule? The use of a 6-day a week schedule has led to expressing GH dose as mg(µg)/kg/week rather than as a daily dose. This expression should be included as an acceptable alternative.
There is insufficient information regarding the safety of doses of GH higher than 2550 µg/kg/day (150300 µg/kg/week), and any recommendation for higher than this "standard" dose should include this caveat.
The all too brief section on safety takes an unwarranted cavalier approach to these issues. Inclusion of the risk factors that predispose to such complications as leukemia, brain tumor recurrence, slipped capital femoral epiphysis, and diabetes would have provided a better context in which to discuss side effects of GH therapy. Those of us who remember discussing the lack of complications and side effects associated with the administration of pituitary GH with parents and patients, only to be blind-sided by the emergence of Creutzfeldt-Jakob disease, maintain a high level of sensitivity regarding potential problems arising with recombinant GH administration. This is particularly the case when the dose of GH is raised above that used in most patients. I find the possible development of Type 2 diabetes mellitus to be of special concern (5).
It is my understanding that the next GRS consensus statement deals specifically with safety issues. It is to be hoped that the discussion will be complete, will not downplay possible complications of GH administration, and will satisfy all of the participants, pessimists as well as optimists, clinicians, and investigators, as well as industrial representatives.
The recommendation that the retesting of patients who have been treated for childhood GH deficiency be done by the pediatric endocrinologist is far too parochial. The deck was stacked in terms of the experience of the conference participants. Surely, this aspect of transition management can be the responsibility of an endocrinologist with training in internal medicine.
What is the general usefulness of consensus guidelines for the clinician? Do they help or hinder the care of an individual patient? At least two points require discussion. I continue to believe that medicine is an intellectual and interpersonal pursuit. Each new patient provides a medical history and physical examination from which the physician constructs a diagnostic hypothesis. This is tested by obtaining a group of laboratory and radiological studies. Eventually, a diagnosis emerges and a course of treatment is chosen. This is an exciting and often frustrating endeavor that, frankly, I find to be great fun. The danger lies in consensus guidelines becoming practice guidelines that metamorphose into an algorithm. This may harden to the point that the physician follows the scheme without paying attention to the patient and without careful thought. The intellectual has become the clerical. Important points may be missed, and the ultimate diagnosis may be incorrect. Flexibility in the application of any guidelines, taking into account the full history and complete physical examination, is essential. Although guidelines may be of considerable clinical value, one must be aware of their potential misapplication.
The second somewhat related problem is the use of guidelines by those who pay for GH treatment. The initial decisions regarding authorization, at least in the United States, are often made my individuals without any clinical background. They are quick to apply existing guidelines under the cloak of "policy." This applies equally to public agencies responsible for paying for health care, HMOs, and the few remaining private health care insurers. Again flexibility in the application of these guidelines is essential if their use as support for the denial of care is to be avoided.
In summary, the GRS guidelines, although still somewhat imperfect, are a valuable contribution to the diagnostic and therapeutic management of GH deficiency. They go a long way toward clarifying any remaining confusion in this complex area of pediatric endocrinology.
Received September 6, 2000.
Accepted September 10, 2000.
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