EDITORIAL
123
Growth hormone deficiency
.......................................................................................
R Ayling
...................................................................................
Is it needed?
G
rowth is controlled and modulated by many factors, including
nutritional, environmental, and
endocrine mechanisms. During the 1st
year of life, nutrition is the most
important factor determining growth.
Growth hormone (GH) is essential for
growth throughout childhood, with sex
steroids contributing to the pubertal
growth spurt.
GH is released from the anterior
pituitary gland under the influence of
the opposing hypothalamic regulatory
peptides, GH releasing hormone
(GHRH) and somatostatin. The actions
of GH are largely indirect, via insulinlike growth factors (IGFs), which exert
negative feedback control on GH
release. The GH releasing peptide ghrelin is the endogenous ligand for the GH
secretagogue (GHS) receptor and
induces a positive energy balance using
an additional mechanism for GH control. It is produced predominantly by the
stomach and appears to have a role in
the integration of energy balance and
growth.
GH DEFICIENCY
GH deficiency (GHD) leads to a reduction in the generation of GH dependent
factors, particularly IGF-I and its major
binding protein IGF binding protein 3
(IGFBP3), which has auxological, clinical, and biochemical sequelae. Children
with GHD are eligible for treatment with
recombinant GH but their definition
remains difficult. This difficulty in definition is reflected by the variability in
prevalence in GHD from 287/million in
the USA, to 20/million in the UK, and by
the large proportion of children diagnosed who are subsequently found to
have normal GH secretion unless strict
auxological and biochemical criteria are
used for diagnosis.1 Short stature may
be the presenting feature of GHD,
characteristically after a period of normal growth, yet the definition of short
stature can itself be difficult.
Assessment of GHD
Assessment of an individual child’s
growth requires information regarding
the limits of normal variability, which
can be obtained by plotting the height
and height velocity on relevant curves
derived from cross sectional and longitudinal data. By comparison with parental height centiles, it can be
determined whether the child is growing appropriately for the family.
Measurement of the skeletal age2 3
allows an estimation of the extent of
future growth. The selection of children
for GH treatment based solely on auxological criteria has been used in
Australia.4 However, physiological interindividual variations in growth rate may
make this an unreliable means of
assessment5 and, in addition, a normal
growth velocity can, in specific clinical
circumstances, be associated with GHD.6
A further problem with the use of
auxological data is that curve fit is poor
at the outer centiles of the curves, where
the least number of data points is
available, and the charts themselves do
not cover the range below the 0.4th
centile, making their use in very short
children inappropriate.
‘‘Children with growth hormone
deficiency are eligible for treatment
with recombinant growth hormone
but their definition remains difficult’’
Imaging of the hypothalamo–pituitary region by computed tomography or
magnetic resonance imaging scanning
forms an important part of the investigation of children with GHD.7 It is
performed to rule out tumours, particularly craniopharyngiomas, and to look
for structural abnormalities that could
be associated with GHD. Structural
abnormalities can be developmental
defects or lesions acquired as a result
of trauma, treatment, or infiltrative
conditions.
Components of the hypothalamo–
pituitary–IGF axis have been investigated as candidates for use in the
diagnosis of GHD. The secretion of GH
from the pituitary is pulsatile, with most
surges occurring during sleep. Between
pulses, plasma concentrations of GH are
low, making random sampling of little
use in the diagnosis of GHD,8 except in
GH stimulation tests
The lack of a suitable replacement has
led to the continued use of GH stimulation tests, although they are non-physiological and not without risk.15 There
is no ‘‘gold standard’’ test, more than 34
having been described, the most frequently cited being clonidine, insulin
induced hypoglycaemia, arginine, glucagon, and GHRH.
There are several fundamental problems with GH stimulation tests. The
GH response used to define deficiency
relies on arbitrary cutoff points, there
are limited data available in children
with normal height velocity, and the
tests have poor reproducibility. In addition, the use of stimulation tests is
further complicated by inherent problems with GH assays. Hence, the results
of two stimulation tests are usually
considered when making a diagnosis of
GHD.
There is no clear definition of what
constitutes a normal rise in plasma GH
after stimulation. Because GH secretion would be expected to cover a
spectrum—from absolute deficiency,
through insufficiency, to normal—any
definition applied would be arbitrary,
and might be expected to show overlap
between normal children and those
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More guidance on growth hormone
deficiency
neonates, where the pulses are of higher
amplitude and frequency.9 Studies of
pulsatile GH secretion can be performed
by serial sampling every 20–30 minutes,
either overnight or for 24 hours, GH
secretion being expressed in various
ways according to the concentrations
obtained from multiple sampling. The
reproducibility of such tests has been
found to be poor, although better than
that of stimulation tests,10 and normally
growing children may have low concentrations.11 Because admission to hospital
is required and the test protocols are
complicated, such tests tend to be
carried out only in specialists units.
The development of sensitive assays
for the low concentrations of GH present in urine has encouraged its use as a
marker of GHD. However, there is overlap in urinary GH concentrations
between normal children and those
with GHD, and the test cannot be used
reliably to discriminate between them.12
Because of their close association with
GH, plasma IGF and IGFBP concentrations have been investigated as markers
of GHD.13 14 IGF-I cannot be used in
infants and is of limited use in younger
children because of its physiologically
low concentrations. Intercurrent illness
and malnutrition can also lower IGF
concentrations. Assuming that these
factors have been considered, an IGF-I
concentration , 2 SD suggests a defect
within the GH axis.
EDITORIAL
124
‘‘The lack of a suitable replacement
has led to the continued use of
growth hormone stimulation tests,
although they are non-physiological
and not without risk’’
Difficulties with the interpretation of
stimulation tests are exacerbated by
problems with the assay of GH resulting
from its molecular diversity. GH is a
polypeptide hormone, with 90% of that
formed in the pituitary being a 22 kDa
form composed of 191 amino acid
residues. The remainder is a 20 kDa
form of 176 residues arising from an
alternative splice site at exon 3. Within
the circulation there are other forms
resulting from post translational modification, metabolic degradation, and
association with GH binding protein.
Differences in assay bias can, in part, be
explained by the ability of the system to
detect 20 kDa human GH, with assays
www.jclinpath.com
using monoclonal antibodies for capture
and detection tending to show less
crossreactivity than monoclonal/polyclonal pairs. It has been recommended that
GH assays should recognise only 22 kDa
GH.24 Although leading to uniformity,
this would result in loss of clinical
information about bioactive GH. Bias
differences between methods could be
reduced by the introduction of a common calibrant,25 and the use of the new
IS 88/624, calibrated in mass units of
22 kDa human GH, has been put
forward.
The need for further guidance in
GHD testing
More than 6000 papers have been
written on biochemical testing in GHD
and paediatricians and clinical biochemists should be aware that it is a
controversial subject. In this issue of
the Journal of Clinical Pathology, Evans
and Gregory26 present the results of a
survey of the investigation of short
stature in Wales and suggest guidelines
to improve practice. Various consensus
documents dealing with the diagnosis of
GHD have already been produced,7 27–32
including that from the GH Research
Society, which gives clear guidelines for
both diagnosis and treatment of GHD.7
One might ask whether further guidance is needed; the results of the
Welsh survey suggest that it is. Evans
and Gregory examined the results of
questionnaires sent to paediatricians
and clinical biochemists in all 13 hospitals in Wales involved in the investigation of children with short stature. They
showed evidence of failure to complete
clinical evaluation before starting investigation and lack of defined investigative protocols. There was a lack of
agreement between paediatricians and
clinical biochemists with regard to the
tests in use, how they should be
performed, and the interpretation of
their results. Although GH was measured in four laboratories, using two
assays, nine different cutoff values were
quoted to define GHD—with paediatricians and clinical biochemists offering
different cutoffs in three centres. The
origin of the cutoff values was stated to
be unknown, unspecified, uncertain
(n = 16), or from published work more
than 15 years old (n = 8). These findings are not unexpected. A recent survey
in Europe showed large heterogeneity in
both clinical and laboratory aspects of
the diagnosis of GHD, particularly with
regard to the standardisation of assays
and the interpretation of cutoff values.33
Previous audits have shown that cutoffs
used in the interpretation of GH stimulation tests are not always related to
method bias.34 35
The diagnosis of GHD is an important
one, which has considerable resource
implications, is relatively arduous, and
potentially dangerous.36 A recent systematic review concluded that it was not
possible to recommend biochemical
tests of GH function in children or offer
advice
on
their
interpretation.37
However in the UK, the National
Institute for Clinical Excellence (NICE)
recommends treatment with recombinant human GH for children with GHD
supported by auxological, biochemical,
and radiological investigations,38 so at
present biochemical investigation of
GHD in children is necessary before
the initiation of treatment.
‘‘The diagnosis of growth hormone
deficiency is an important one,
which has considerable resource
implications, is relatively arduous,
and potentially dangerous’’
Although guidelines may not be
wholly applicable outside the unit in
which they were written, and may
require flexibility in their application to
individual patients, those proposed here
cover the initial investigation of short
stature, provocation testing, and retesting after attainment of final height,
and could certainly make a useful
contribution to practising within the
NICE framework.
J Clin Pathol 2004;57:123–125.
doi: 10.1136/jcp.2003.8029
Correspondence to: Dr R Ayling, Department of
Clinical Chemistry, Derriford Hospital,
Plymouth, Devon PL6 8DH, UK;
ruthayling@clinicalbiochemistry.org.uk
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125