Transcript Endocrine Compliction in Thlassaemia Major: Growth & Puberty

Endocrine Complication in
Thalassaemia Major:
Growth & Puberty
Dr Wong Lap Ming
Department of Paediatrics & Adolescent Medicine
Tuen Mun Hospital
15-7-2004
• Iron overload leads to formation of free
radicals which damage membrane lipids
and other macromolecules, leading to
cellular damage and necrosis.
Prevalence of endocrine disturbance in
165 patients with thalassaemia major*
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Secondary amenorrhoea
50%
Hypogonadotrophic hypogonadism 43%
Short stature
34%
Impaired glucose tolerance
24.7%
IDDM
18.8%
Primary hypothyroidism
9%
GH deficiency/insufficiency
6%
Hypoparathyroidism
5%
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* De Sanctis. Growth and Puberty and its Management in Thalassaemia. Horm Res 2002;58(suppl 1):72-79
Causes of short stature
• Chronic anaemia, hypersplenism, folate deficiency.
• Endocrine disturbance owing to iron overload (
Growth hormone axis, hypothyroidism &
hypogonadism)
• Chronic liver disease
• Bone dysplasia owing to desferrioxamine
# Diminished spinal growth mainly accounts for the
short stature.
Iron concentration per gram of liver dry weight
< 3mg
risk of toxicity owing to chelating agent
5-15mg risk of organ damage
>15mg cardiomyopathy & death
Desferrioxamine toxicity
• Desferrioxamine inhibit DNA synthesis, fibroblast
proliferation, collagen formation & zinc deficiency.
• Bone dysplasia manifested as bone pain, back pain,
limited joint movement, reduction in height velocity,
platyspondylosis (short spine), widened growth plate
( especiallly in wrist & knee).
Desferrioxamine toxicity, radiological
changes
• Thickened growth plate with widening & cupping of
metaphysis
• Sclerosis of sub-chondral bone with small
radiolucent areas in metaphyses.
• Osteoporosis & increased trabecular pattern of long
bones.
Zinc deficiency
Growth retardation
Delayed bone maturation
Hypogonadism
Growth pattern of thalassaemia major
• Childhood : normal height velocity
• 8-9 years : decreased height velocity
• Pubertal : absent or suppressed growth spurt
* There is decreasing upper to lower segment ratio
during puberty as a result of diminished spinal
growth.
* Height gain can be prolonged until 20s, but the final
height is often more than 2.5SD below the mean.
GH axis disturbance (1)
• High/normal/reduced GH response to stimulation
test
• Reduced spontaneous secretion (neurosecretory
dysfunction)
• Low IGF-1 level despite normal GH level ( owing to
liver disease)
• Treatment with GH is with variable success,
depending on underlying cause for the short stature.
GH axis disturbance (2)
• The low IGF-1 in short patient with GH reserve
suggested defect in GH-receptor or post-receptor
abnormality.
• Supra-physiological doses of GH resulted in subnormal rise in IGF-1 level suggesting that short
stature might not be corrected by GH treatment.
Suggested management approach*
• Investigations
Auxology: standing & sitting height, pubertal stage
Bone age
GH stimulation test, IGF-1 & IGFBP-3 if available
TSH, fT4
R/LFT CaPo, serum zinc, serum ferritin
* Wonke B, De Sanctis V. Haemoglobinopathies. In Kelnar CJ, Savage MO, Stirling HF, Saenger P. Growth
disorders,pathophysiology and treatment. Chapman & Hall Medical, 1998:471-482.
Suggested management approach*
• Recombinant human GH ( 0.6-0.8 IU/kg per week in
pre-pubertal, 0.9 IU/kg per in pubertal)
Responder: height velocity >4cm/yr greater than
previous yr.
Partial responder: height velocity 2-4cm/yr greater
than previous yr
Non-responder: height velocity <2cm greater than
previous yr
* Final height gain remains uncertain.
** Wonke B, De Sanctis V. Haemoglobinopathies. In Kelnar CJ, Savage MO, Stirling HF, Saenger P. Growth
disorders,pathophysiology and treatment. Chapman & Hall Medical, 1998:471-482.
Hypogonadism
• The most common endocrine disturbance.
• Causes:
Pituitary gonadotrophs damage
Gonadal damage
Liver disease
Chronic hypoxia
DM
Zinc deficiency
Evidence of pituitary damage
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Histological finding of reduced numbers of cells.
Selective iron deposition in gonadotrophic cells
Mean Pituitary volume lower as detected by MRI.
Reversal of hypogonadotrophic hypogonadism after
removal of iron overload is rare.
• In contrast, iron deposition in gonads do not have a
significant negative effect on function.
Presentation
• Female: poor/absent breast development, delayed
menarche, oligomenorrhoea or secondary
amenorrhoea.
• Male: failure of testicular and penile
enlargement,sparse facial and body hair, decreased
libido.
Assessment
• Auxology: standing & sitting height, pubertal stage,
bone age.
• Serum LH & FSH before & after GnRH stimulation.
• Serum estradiol & testosterone.
Induction of puberty
• Female: (may start at chronological age of 13, bone
age of 10-11 yr)
Ethinylestradiol 2.5-5 mcg daily for 3-6 months.
If there is no evidence of biochemical pubertal
progress, a gradual increase of sex steroid is
recommended , follows by cyclical estrogen &
progesterone.
• Male:
Sustanon 25-50 mg per month for 3-6 months. If
puberty does not progress spontaneously, treatment
is continued with gradual increase in dose.