 |
| Resources |
 |
|
|
|
|
|
TREATMENT OF GH DEFICIENCY IN CHILDREN
Introduction
- The diagnosis of severe GH deficiency
(GHD) is usually straightforward, as there are well-defined
clinical, auxological, biochemical and radiological abnormalities.
- It is recognised however that
the diagnosis of moderate GHD can be difficult. It is very important
that response to recombinant human (rh)GH treatment in this
group is carefully reviewed.
The Process of Evaluation
of the GH-IGF Axis
- In a child with slow growth, whose
history and auxology suggest GHD, testing for GH/IGF-I deficiency
requires IGF-I/IGFBP-3 levels and GH provocation tests after
hypothyroidism has been excluded. IGF-I would be considered
superior to IGFBP-3 for diagnostic purposes.
- In suspected isolated GHD, two
GH provocation tests (sequential or on separate days) are required.
However in those with defined CNS pathology, history of irradiation,
multiple pituitary hormone deficiency (MPHD) or a genetic defect,
one GH test will suffice.
- In a child with clinical criteria
for GHD peak GH concentrations below 10m g/L have traditionally
been used to support the diagnosis. However this value will
vary dependent on the assay used and needs to be revised downwards
when using newer monoclonal-based assays and recombinant hGH
reference preparations.
- Values below a cut-off <-2SD
for IGF-I and/or IGFBP-3 strongly suggest an abnormality in
the GH axis, if other causes of low IGF have been excluded.
Nevertheless in GHD values of IGF-I and IGFBP-3 within the normal
range can occur. In the absence of a gold standard, it is therefore
important that the clinician integrates all available data (clinical,
auxological, radiological and biochemical) when making a diagnosis.
- In addition, an evaluation of
other pituitary function is required.
- In patients who have had cranial
irradiation, GHD may evolve over years and its diagnosis may
require repeat testing of the GH-IGF axis.
- It is recognized however that
some patients with auxology suggestive of GHD may have IGF-I
and/or IGFBP-3 levels below the normal range on repeated tests
but GH responses in provocation tests above the cut-off level.
These children are not classically GH deficient but may have
an abnormality of the GH/IGF axis, and after the exclusion of
systemic disorders affecting the synthesis or action of IGF-I,
could be considered for GH treatment.
- A MRI of the brain with particular
attention to the hypothalamic-pituitary region should be carried
out in any child diagnosed as having GHD.
Treatment Objectives
- Patients with proven GHD should
be treated with recombinant human GH as soon as possible after
the diagnosis is made. The primary objectives of the therapy
of GHD are normalization of height during childhood and attainment
of normal adult height.
- Patients who have well-documented
evidence of GHD but are growing normally (such as those with
craniopharyngioma or midline developmental defects) should be
considered for therapy with GH for metabolic and body composition
benefits and for enhancement of pubertal growth.
- Insufficient data regarding
the utility of GHRH and GH-secretagogues are currently available
to formulate recommendations regarding their use in GHD.
Dosing of GH
- GH should be administered
subcutaneously on a daily basis and the dosage of GH should
be expressed in mg (or m g)/kg/day although consideration
should be given to dosing in m g/m2/day in patients
with obesity.
- GH is routinely used in the
range of 25-50 m g/kg/day. A dose-response relationship
in terms of height velocity in the first two years has been
clearly demonstrated within this range. Under special circumstances,
higher doses may be required.
- Prediction models of growth
response might be useful for determination of the optimal individual
dose and are currently being investigated but need further evaluation.
Monitoring GH therapy
- The routine follow up of paediatric
GHD patients should be performed by a paediatric endocrinologist,
in partnership with the general paediatrician and/or the general
practitioner, and be conducted on a 3-6 month basis.
- The determination of the growth
response to GH treatment is the single most important parameter
in the monitoring of the child with GHD. Increase in height
and change in height velocity are useful in clinical practice
to assess the response to GH. For comparative purposes in audit
or clinical studies, data should be expressed as the increase
in (or delta) height SD/year.
- For assurance of compliance
and for the recognition of supranormal values, monitoring serum
IGF-I and IGFBP-3 levels is proposed. However it is recognised
that changes in these peptides during rhGH treatment do not
always correlate well with the growth response. The frequency
of such monitoring has not been determined, but it is suggested
that annual evaluation could be undertaken. More evidence for
the value of these tests is required.
- The routine monitoring of
GH antibodies has no value in GHD management. Lipid profiles
and fasting insulin levels are not routinely measured in the
child receiving GH therapy.
Factors affecting
the response to GH
- Every effort should be made
to diagnose and treat children at the youngest possible age.
It is very important to maximize height with GH therapy before
the onset of puberty.
- Treatment of children entering
puberty at an inadequate height, using GH dose escalation, or
combined GH and gonadotrophin releasing hormone (GnRH-)agonist
therapy, is presently being evaluated.
- In the MPHD patient in whom
puberty does not occur spontaneously, puberty should be initiated
at the appropriate time after discussion with the patient.
Management of MPHD
- Patients with suspected or
proven multiple pituitary hormone deficiencies should be managed
similarly to patients with isolated GHD (IGHD); however, attention
should be given to correct clinical recognition, treatment,
and monitoring of additional hormonal deficiencies (thyroxine,
cortisol, sex steroids and ADH).
- In the patient with an initial
diagnosis of isolated GHD particularly those with an ectopic
posterior pituitary or other developmental abnormalities, the
clinician should be alert to the risk of the development of
MPHD.
Safety issues
- Growth hormone increases the extrathyroidal
conversion of T4 to T3 and may as such unmask incipient hypothyroidism.
Monitoring of thyroid function should therefore be conducted
in all patients. GH may decrease serum total cortisol concentrations
by decreasing circulating cortisol binding globulin. GH may
also reduce the bioavailability of cortisol through an enhanced
net conversion of cortisol to cortisone. Even though the clinical
implications for these observations are uncertain, increased
awareness of glucocorticoid status is recommended in all patients.
The possibility that overt ACTH insufficiency may be unmasked
during GH replacement should be considered.
- Significant side effects of
GH treatment in children are very rare. These may include benign
intracranial hypertension, prepubertal gynaecomastia, arthralgia,
and oedema. Careful history and physical examination are adequate
to identify their presence. Management of these side effects
may include either transient reduction of dosage or temporary
discontinuation of GH.
- In the absence of other risk
factors there is no evidence that the risk of leukemia, brain
tumor recurrence and slipped capital femoral epiphysis are increased
in recipients of long-term GH treatment. Tumour survivors receiving
GH should be followed in conjunction with an oncologist and
a neurosurgeon when appropriate.
- At present there is no substantial
evidence that rhGH replacement treatment in IGHD and MPHD leads
to an increased incidence of non-insulin or insulin dependent
diabetes mellitus.
- There is no evidence that GH
replacement needs to be discontinued during intercurrent illness,
nor are there data to support
discontinuation of appropriate GH replacement in patients receiving
intensive care treatment for critical illness.
- It is essential that all possible/probable
adverse events of rhGH are reported through the Yellow Card
system. The acquisition of very long-term safety data for rhGH
is essential.
Transition to adult
management
- After attainment of final
height, retesting of the GH-IGF axis, using the adult GHD diagnostic
criteria as defined by the Growth Hormone Research Society (GRS)
consensus workshop on adult GHD in 1997 at Port Stephens should
be undertaken by the paediatric endocrinologist using standard
GH stimulation tests after an appropriate interval of 1 to 3
months off GH therapy.
- At the time of retesting,
other pituitary hormones and an IGF-I should also be measured.
The opportunity should be taken to assess body composition,
bone mineral density, fasting lipids and. Quality of life should
be assessed using validated age and disease appropriate instruments,
which at this time require development.
- Patients with severe long
standing MPHD, those with genetic defects, and those with severe
organic GHD can be excluded from GH-retesting.
- GH has major metabolic actions,
which are important for body composition and health in adults
as in children. When the diagnosis of adult GHD is established,
continuation of GH therapy is recommended.
- Caution should be exercised
when considering the decision of continuing GH therapy in conditions
where there is a known risk of diabetes or malignancy.
- The transition to adult GH replacement
should be arranged as a close collaboration between the paediatric
and adult endocrinologists who should discuss the re-initiation
of treatment with the patient.
|
|
|
