Ann Hematol (2003) 82:637–640 DOI 10.1007/s00277-003-0712-3
O R I G I N A L A R T I C L E
K. H. Wu · F. J. Tsai · C. T. Peng
Growth hormone (GH) deficiency in patients with b-thalassemia major
and the efficacy of recombinant GH treatment
Received: 4 April 2003 / Accepted: 3 June 2003 / Published online: 31 July 2003 Springer-Verlag 2003
Abstract
Patients with b-thalassemia major still suffer
growth retardation. After excluding patients with cortisol
deficiency, hypothyroidism, hypogonadism, delayed
pu-berty, malnutrition, severe congestive heart failure, and
severely impaired liver function, 29 patients were
enrolled in this study. Fifteen (52%) patients exhibited
growth retardation and underwent two growth hormone
(GH) provocation tests. Eight (53%) of the 15 patients
had GH deficiency and were subsequently treated with
subcutaneous recombinant
human GH (Genotropin,
Pharmacia Corporation, Sweden). Growth velocity
in-creased from the pretreatment rate of 3.1€0.4 cm/year to
7.1€1.6 cm/yr (p<0.001) after 1 year and to 6.8€1.3 cm/
year (p<0.001) after 2 years. Patients with growth
retardation had lower insulin like growth factor-1
(p=0.001) and insulin like growth factor binding
pro-tein-3 (p=0.003) levels than those without growth
retar-dation. In patients with b-thalassemia major, growth
retardation is a common complication and GH deficiency
plays an important role. Thalassemic patients with GH
deficiency can safely increase their growth velocity with
recombinant human GH for2 years; however, the effect
on final height still needs to be determined.
Keywords
b-thalassemia major · Growth hormone (GH)
deficiency · Recombinant human GH
Introduction
The inherited hematological condition b-thalassemia
major is not uncommon in Taiwan. Recent medical
advances have improved the survival rate of thalassemic
patients [1], but endocrine disturbances, specifically
growth retardation, are a common problem for sufferers.
Many factors have been proposed as causes of growth
retardation—the disease itself, the toxic effects of
desferrioxamine [2, 3], iron toxicity, malnutrition [4, 5],
and endocrine dysfunction—but the mechanisms
respon-sible for growth retardation in these patients have not yet
been fully elucidated.
As far as endocrine dysfunction is concerned, apart
from thyroid function and the gonads [6, 7], the Growth
Hormone (GH)-Insulin Like Growth Factor (IGF)-Insulin
Like Growth Factor Binding Protein (IGFBP) axis is
believed to play an important role in growth retardation
[8, 9]. Both normal and subnormal GH responses to
provocation stimulation tests have been previously
re-ported [10, 11, 12, 13, 14, 15]. Estimating the circulating
concentrations of IGF-1 and IGFBP-3 allows more
accurate evaluation of the GH-IGF-IGFBP axis. Recent
reports indicate that treatment of patients with
b-thalas-semia major with recombinant human GH (rhGH) can
lead to significant improvements in growth [8, 9, 10, 11,
16, 17, 18, 19].
Patients and methods
After excluding patients with hypothyroidism, hypogonadism, delayed puberty, malnutrition, severe congestive heart failure, and severe impairment of liver function, 29 patients with b-thalassemia major were enrolled in the study. There were 16 males and 13 females; mean age was 11.2€4.3 years (range: 5.3 to 21.9 years). All received regular transfusions to maintain pre-transfusion hemoglobin levels above 10 g/dl and desferroxamine was subcu-taneously administered for iron chelation (duration: 8–12 h; 5 days/ week) at a dose of 30–50 mg/kg/day depending on serum ferritin levels.
Patient heights were measured using standard anthropometric techniques with a wall-mounted stadiometer and the height was categorized according to published local curves [20]. Bone age was determined in accordance with the published methods of Greulich and Pyle [21]. Serum IGF-1 and IGFBP-3 levels were measured with an immunoradiometric assay supplied by Diagnostic Systems Laboratories (Webster, Texas, USA), and we defined low serum IGF-1 and IGFBP-3 as a level below the 3rd percentile.
Patients with growth retardation (body height 2 SD below the mean) underwent two separate GH provocation tests using either K. H. Wu · F. J. Tsai · C. T. Peng (
)
)Department of Pediatrics, China Medical College Hospital, 2 Yuh-Der Road, 404 Taichung, Taiwan e-mail: [email protected] Tel.: +886-4-22052121
clonidine or insulin hypoglycemia on two different days to assess GH response. After oral clonidine administration at a dose of 0.1 mg/m2, blood samples were collected at 0, 30, 60, 90 and
120 min for GH measurement. Insulin was intravenously admin-istered at a dose of 0.12 unit/kg to induce hypoglycemia. GH was measured at 0, 20, 40, 60, 90 and 120 min after insulin administration. Plasma GH was measured using the aforementioned immunoradiometric assay. In patients with growth retardation, a peak GH level of less than 10 mg/ml on both tests and bone age delays of more than 2 years was indicative of GH deficiency.
Patients with GH deficiency were treated with subcutaneous rhGH (Genotropin, Pharmacia Corporation, Sweden) doses of 0.1 IU/kg/day for 2 years. Anthropometric measurements, blood pressure, fasting blood glucose, and renal function were assessed at entry and then monthly. Compliance was assessed by self-report and the return of used drug vials.
Data are presented as means€standard deviation (SD). The results were analyzed by analysis of variance followed by the Student’s t-test. The paired t-test was used to compare data before and after therapy in the same group. Differences in serum IGF-1 and IGFBP-3 between thalassemic patients with and without growth retardation were analyzed with the Chi-Square tests and Fisher’s Exact test. A p value of less than 0.05 was considered significant.
Results
Twelve patients from the group of 41 patients with
b-thalassemia major who had regular follow up at our
hospital were excluded for the following reasons: three
cases were due to delayed puberty, two cases due to
hypothyroidism, three cases due to diabetes, two cases
due to hypogonadism, and two cases due to severe heart
failure. After the exclusion, 29 patients were enrolled.
The results of comparisons of gender, chronologic age,
bone age, delayed bone age, growth velocity, serum
ferritin, and alanine aminotransferase in patients with and
without growth retardation are summarized in Table 1.
Variables in patients with growth retardation were not
significantly different from those without growth
retar-dation except for delayed bone age (2.4€1.4 vs.
1.4€1.3 years, p=0.02) and growth velocity (3.1€0.4 vs.
6.3€1.5 cm/yr, p=0.006).
Table 2 lists serum IGF-1 and IGFBP-3 levels for
patients with and without growth retardation. Our study
results indicate that the proportion of subjects with low
IGF-1 (c
2=18.34, p=0.001) and IGFBP-3 (c
2=10.21,
p=0.003) in the growth retardation versus the non-growth
retardation group were significantly different.
Of the 29 patients, 15 (52%) patients were found to
have growth retardation. Among these 15 patients who
then received the two GH provocation tests, eight patients
(53%) were found to have GH deficiency. Subsequently,
these eight patients underwent rhGH therapy. Growth
velocity in the rhGH-treated subjects increased from the
pretreatment rate of 3.1€0.4 cm/yr to 7.1€1.6 cm/yr
(p<0.001) after 1 year and to 6.8€1.3 cm/yr (p<0.001)
after 2 years(Table 3). None of the rhGH-treated patients
developed hypertension, fasting hyperglycemia,
leuke-mia, pseudotumor cerebri, or renal function impairment.
Discussion
Thanks to medical advances, prolongation of life
expect-ancy in patients with b-thalassaemia major is possible, but
quality of life issues become important. Many causes of
growth retardation have been proposed, but mechanisms
are not yet fully understood. In this study, patients with
Table 1 Parameters compared between thalassemic patients with and without growth retar-dation
Growth retardation (n=15) No growth retardation (n=14) p valuea Gender
Male (n=16) 9 7 0.59b
Female (n=13) 6 7
Chronologic age (yr) 12.2€2.6 10.0€5.5 0.18
Bone age (yr) 9.8€2.2 8.9€5.2 0.10
Delayed bone age (yr) 2.4€1.4 1.4€1.3 0.02*
Growth velocity (cm/yr) 3.1€0.4 6.3€1.5 0.006*
Serum ferritin (ng/ml) 3791.3€1702.3 3209.5€2206.5 0.43
ALT (U/l) 28.1€11.8 27.6€15.2 0.91
Values are presented as mean€SD.
ALT alanine aminotransferase (normal value: 0–40 U/l), n case number * p<0.05
a
Student’s t-test
b
Chi-square test
Table 2 Serum IGF-1 and IGFBP-3 compared between patients with and without growth retardation GR (n=15) No GR (n=14) c2statistic p value Low IGF-1 13 (86.7%) 1 (7.1%) 18.34 0.001* Normal IGF-1 2 (13.3%) 13 (92.9%) Low IGFBP-3 11 (73.3%) 2 (14.3%) 10.21 0.003* Normal IGFBP-3 4 (26.7%) 12 (85.7%)
We defined low serum IGF-1 and IGFBP-3 as a level below the 3rd percentile. GR growth retardation, n case number
*p<0.05 638
cortisol deficiency, hypothyroidism, hypogonadism,
de-layed puberty, malnutrition, severe congestive heart
failure, and severely impaired liver function were
ex-cluded, and the hemoglobin level of all subjects was kept
above 10 g/dl. Even after excluding patients with the
above conditions, 52% of our study subjects were found
to have growth retardation.
The GH-IGF-IGFBP axis is now thought to play an
important role in growth retardation, but agreement has
not been reached regarding the exact GH-IGF-IGFBP axis
abnormality responsible. Using classical GH provocation
tests, the GH reserve has been reported to be normal, or
reduced. Wonke (1998) et al. reported that growth
retardation in iron-overloaded patients is the result of
GH deficiency in up to 30% of patients [22]. In our study,
15 patients with growth retardation received two separate
GH provocation tests, and eight patients (53%) were
found to have GH deficiency. This finding tends to
confirm that while not the only reason, GH deficiency
plays an important role in growth retardation in patients
with b-thalassemia major.
Determination of serum IGF-1 and IGFBP-3 levels
promises to be of considerable value in the assessment of
GH-IGF-IGFBP axis disorders [23, 24]. We found that
patients with growth retardation were more likely to have
low IGF-1 and IGFBP-3 than those without growth
retardation. Therefore, the defective GH-IGF-IGFBP axis
in patients with b-thalassemia major is associated with
growth retardation [8, 9].
We found some growth-retarded patients with low IGF
levels but without GH deficiency in this study. Serum IGF
is produced by the liver and is subject to GH regulation.
Hepatic injury in IGF biosynthesis has been suggested as
one explanation of growth retardation in thalassemic
patients [13]. The elevation of ALT results from acute
destruction of hepatic cells. Hepatic injury in thalassemic
patients mainly results from iron storage and it is not
acute. Therefore, although the mean ALT did not elevate
in these patient, hepatic injury in patients with
b-thalassemia major might be the cause of low IGF levels
in growth-retarded patients without GH deficiency.
Treatment using rhGH has been used for short
thalassemic patients with a normal GH reserve or with
GH deficiency [8, 9, 10, 11] and has been shown to
increase growth velocity irrespective of any GH
deficien-cy [16, 17, 18, 19]. Whether the final height of these
thalassemic patients increases after rhGH treatment is an
interesting issue. The duration of treatment in most
previous studies was 1 year. Cavallo et al. reported that
the encouraging results described from the first year of
rhGH treatment did not persist during the second and third
years [19]. However, our study showed that the growth
velocity continue to increase in the second year of
treatment in thalassemic patients with GH deficiency. No
side effects of rhGH therapy were observed during
treatment; therefore, rhGH therapy is safe for at least
2 years.
In conclusion, growth retardation is a common
prob-lem in patients with b-thalassemia major. When
investi-gating the GH-IGF-IGHBP axis, GH deficiency was
found to play an important role. In addition to GH
deficiency, we found that serum IGF and IGFBP-3 levels
are associated with growth retardation. Treatment with
rhGH can safely increase growth velocity for 2 years, but
it remains to be elucidated whether long-term
adminis-tration will affect the final height. We are currently
evaluating the effect of long-term rhGH therapy.
AcknowledgementsWe would like to thank Miss Tsai-Chung Li, a teacher at the institute of Chinese Medicine at the China Medical College in Taichung, for her statistical assistance and interpretation.
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