Pediatric Hematology Oncology Journal 2 (2017) 98e106
Contents lists available at ScienceDirect
Pediatric Hematology Oncology Journal
journal homepage: https://www.elsevier.com/journals/pediatric-
hematology-oncology-journal/
Growth and endocrine issues in children with thalassemia
Preeti Singh, Anju Seth*
Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India
a r t i c l e i n f o
Article history:
Received 9 October 2017
Received in revised form
18 December 2017
Accepted 19 December 2017
Available online 20 December 2017
1. Introduction
With the advent of intensive transfusion and chelation regimes,
life expectancy has increased significantly in patients with b-
thalassemia major (TM). However, progressive iron deposition in
tissues as a result of repeated blood transfusions and enhanced
dietary absorption of iron due to ineffective erythropoiesis leads to
many complications that may emerge as these children grow into
adolescence and adulthood. The deleterious effects of excessive
iron deposition are primarily observed in the heart, liver and
endocrine organs like pituitary- gonadal axis, GH-IGF axis, thyroid,
parathyroid, pancreas and adrenals. Thus, in this era, the endocrine
complications have emerged as an important cause of morbidity
and an important determinant of quality of life in children with TM.
The earliest case of multiple endocrine dysfunction in thalas-
semia intermedia was reported around 50 years ago [1]. The data
on prevalence of endocrine dysfunction in patients with TM is
limited and shows a wide variation due to differences in the study
cohorts, age at onset of transfusion and chelation and compliance
to both. The predominant clinical phenotypes include short stature,
delayed/arrested puberty, abnormal bone mineralisation, impaired
glucose tolerance, hypothyroidism and hypoparathyroidism.
Table 1 shows the comparative prevalence of endocrine complica-
tions reported in children with TM in various settings over last 2
* Corresponding author. Lady Hardinge Medical College and Kalawati Saran
Children’s Hospital, Shaheed Bhagat Singh Marg, New Delhi, India
E-mail addresses: drpreetisingh3@gmail.com (P. Singh), anjuseth.peds@gmail.
com (A. Seth).
Peer review under responsibility of Pediatric Hematology Oncology Chapter of
Indian Academy of Pediatrics.
https://doi.org/10.1016/j.phoj.2017.12.005
2468-1245/© 2018 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Publishing Services by Elsevier B.V. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
decades [2e7].
The underlying patho-physiological mechanism underlying
these complications is excessive iron load, a consequence of
repeated blood transfusions that these children receive from early
childhood. Endocrine glands have high levels of transferrin re-
ceptors that promote iron accumulation and hence increase
vulnerability of these glands to iron toxicity. Iron stored in endo-
crine glands binds to intracellular transferrin. As the storage ca-
pacity of transferrin gets exceeded, pathological quantities of
metabolically active iron catalyses formation of free radicals, which
in turn damage intra-membrane lipids and other macro-molecules,
ultimately causing cell death and organ failure. The degree and the
severity of iron toxicity depends upon the frequency/need for
transfusions determined by genotype of the individual, the age at
initiation of chelation therapy and compliance to it [8].
In this review, we present an overview of the various endocrine
dysfunctions observed in patients with TM.
2. Growth failure
Growth failure is one of the most common co-morbidities wit-
nessed in children and adolescents with TM and an important
cause of poor body image in these children. The prevalence of
growth failure and short stature in children with thalassemia varies
from 30 to 50% in most studies [2]. The causes are multifactorial.
The key factors responsible for growth disturbances are summa-
rized in Table 2. The relative contribution of various factors may
vary at different ages. Chronic anaemia, hypoxia and nutritional
factors are usually operational before 5 years especially in children
who do not receive regular transfusions. Between 5 and 10 years,
the adverse effects of transfusion associated iron overload on linear
growth (GH-IGF-1 axis) are apparent in the absence of adequate
chelation. Beyond the age of 10 years, absent/reduced pubertal
spurt due to involvement of hypothalamo-pituitary-gonadal (HPG
axis) axis makes a significant contribution. At all stages, co-
morbidities can add further adverse influence [9]. Children who
are well transfused and adequately chelated have the best prog-
nosis for reaching optimum height.
In the current era, children receiving regular blood transfusions
and optimal chelation therapy usually do not exhibit signs of
growth failure until the end of first decade. Most patients with poor
growth present either in the peri-pubertal phase with impaired
 P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106
Table 1
Comparative prevalence of endocrinal complications of children with TM.
Cyprus [2] Italy (1995) [3] Iran (2003) [4]
Number of Patients 435 1861 220
Hypogonadism (%) 32.5 49 22.9 (males), 12.2 (females)
Short Stature (%) 35 39.3
Sitting Height (%) 72
Hypothyroidism (%) 5.9 6.2 7.7
Hypoparathyroidism (%) 1.2 3.6 7.6
DM/IGT (%) 9.4 4.9 8.7
Table 2
Factors contributing to growth failure in children and adolescents with TM.
a. Chronic anaemia with ineffective erythropoiesis
b. Under nutrition (Zinc Deficiency)
c. Iron overload resulting in chronic liver disease and cardiac dysfunction
d. Transfusion associated infections like hepatitis C, B, HIV
e. Endocrinal dysfunctions- Defective GH-IGF-1 axis
Defective Pituitary-Gonadal axis
Hypothyroidism, hypoparathyroidism
Diabetes mellitus
f. Side effects of chelation therapy on skeletal growth
g. Psychosocial stress
growth or during puberty with arrested or absent puberty and
absence of growth spurt. The growth plate fusion is also delayed in
these children until the end of second decade and thus they have a
potential for growing when most unaffected children have
completed their growth. This is primarily due to iron load affecting
the Growth Hormone e Insulin like Growth Factor axis (GH-IGF
axis) and the HPG axis. The anterior pituitary is particularly sen-
sitive towards free radical oxidative stress from iron toxicity.
The short stature (SS) encountered in thalassemia is often
disproportionate with a low upper segment to lower segment ratio
[10]. The exact reason is not clear and an interplay of multiple
factors are responsible for it. In thalassemia, there is a progressive
impairment in spinal growth observed since early childhood [11].
Besides, other factors implicated in body disproportion include iron
overload (impaired cartilage growth), early use of desferrioxamine
(DFO) for chelation and delayed puberty (hypogonadism). Use of
DFO between 2 and 5 years has a paradoxical adverse effect on
growth through inhibition of cell proliferation, DNA synthesis, and
collagen formation and trace mineral deposition like Zn and Cu
resulting in flattening of vertebrae (platyspondylosis) and reduced
spinal height [12]. Short trunk, genu valgum, metaphyseal
widening and joint stiffness is noted. The radiological changes seen
are thickened growth plates with widening and cupping of meta-
physes, sclerosis of subchondral bone with small radiolucent areas
localised to the metaphyses and osteoporosis and increased
trabecular pattern of long bones. Off late, deferiprone treatment has
been reported to be associated with arthropathy mainly of the
knees [13,14]. MRI studies indicate that damage to the cartilage and
the subchondral bone persist despite stopping treatment.
Several mechanisms influencing the Growth Hormone
Releasing Hormone (GHRH)-GH-IGF- axis have been proposed to
explain the growth faltering in patients with TM [15]:
(1) Hypothalamic GH-releasing hormone deficiency (2) pitui-
tary GH deficiency; (3) neurosecretory dysfunction and (4) relative
GH insensitivity. Growth Hormone deficiency (GHD) is seen in
20e30% of thalassemia patients while the remaining 70e80% show
a peak growth hormone levels lower than those found in patients
with constitutional short stature in response to GH provocative
stimuli like clonidine. Children with TM exhibit low IGF-1 levels in
both GH deficient (GHD) and GH sufficient (GHS) subgroups. This
99
TIF (2004) [5] North America (2004) [6] India (2014) [7]
3817 342 89
40.5 35 54.1
30.8 55
3.2 9 8.9
6.9 4 10.1
3.2/6.5 10 13
was evident from a prospective study to assess the age related
changes in serum IGF-1 concentrations in thalassemia patients
compared to age and sex matched normal cohort. The normal
healthy cohorts experienced a peak in IGF-1 levels at 13 years
(boys) @ 8e9 times the baseline. The thalassemia patients with
GHD did not show peak rise in IGF-1 levels till 18 years while the
subgroup with GHS reported a late and attenuated peak IGF-1
levels at 16e18 years (@ 3 times from baseline) [16]. Further, the
IGF-1 response to exogenous administration of GH is significantly
lower in children with thalassemia and GHD as compared to ones
who have idiopathic GHD [17]. There is another subgroup of thal-
assemia children who show a normal GH response to provocative
tests but their IGF-1 levels continue to be low suggesting a low GH
sensitivity (secondary to liver dysfunction) or a neurosecretory
dysfunction. The latter manifests as an abnormal nocturnal GH
secretory pulse pattern (due to high somatostatin tone) and lack of
negative feedback regulation (in response to low IGF-1 levels) at
the hypothalamus-pituitary level [17].
Puberty (spontaneous/induced) plays a significant role in
achieving the desired growth spurt in adolescents by augmenting
the GH pulse amplitude that leads to a rise in IGF-1 and IGF-BP-3
levels. There is a mutual amplifying effect in the concentration of
GH, IGF-1 levels and sex steroids observed during the progressive
stages of puberty that results in growth spurt, appearance of sec-
ondary sexual characteristics, increase in muscle mass and bone
mineral accretion. Children with thalassemia experience delay/ar-
rest in puberty due to the hypogonadotropic hypogonadism with or
without loss of gonadal function [18].
2.1. Growth monitoring in children with thalassemia
1. A longitudinal record of weight and height (along with Mid
parental height (MPH) and Target range) and BMI should be
maintained on a growth chart at six monthly interval to facilitate
early detection of growth faltering. MPH is calculated by adding
6.5 cm to the average of the mother's and father's height in the case
of boy and by subtracting 6.5 cm in the case of girl. Statistically 95%
of the children are expected to reach an adult height within a range
of about 8.5 cm above or below the MPH percentile (i.e. ±2SD on
either side of MPH). This range is called as Target range. The annual
growth velocity (GV) is assessed, if < 25th percentile consider it a
red flag.
2. Compare the height indices (height for age) of the patient
(height SDS or centiles) with the population data as well as with the
mid-parental height (SDS or centiles).
2.2. Definition of short stature
 Height is less than the 3rd percentile or 2 SD below the mean
height for age and sex; OR
 Height is within normal but GV is consistently <25th percentile
over 6e12 months; OR
100 P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106

 The patient is excessively short for his/her mid-parental height,
though his absolute height may be within the normal
percentiles.
3. Assess for onset and progress of puberty (SMR using Tanners
staging) annually for all children above 10 years of age. The varied
phenotypes of pubertal delay are described in Table 3.
2.3. Assessment in a child with short stature
i. Treatment of anaemia and optimizing chelation therapy.
ii. Correction of nutritional deficiencies if any, undernutrition
and mineral deficiencies (zinc)
iii. Treatment of overt hypothyroidism
iv. GH treatment is indicated in established cases with GH
deficiency.
v. Timely replacement therapy with sex steroids in children
with failure of spontaneous pubertal onset/poor progression
of puberty.
vi. Psychosocial support

1. The following points in HISTORY should be inquired in a child

who has TM.
 Onset of disease and the need for blood transfusions
 Pre-transfusion haemoglobin level
 Annual packed cell volume requirement
 Chelation type, dose, compliance
 Serum ferritin levels
 Any associated comorbidity like features suggestive of endo-
crine complications or coinfection with blood borne agents
like Hepatitis B, C or HIV.
2. The EXAMINATION would include:
 General Physical Examination: A note is made on the skin
pigmentation, pallor, icterus, cyanosis, clubbing, and
thyromegaly.
 Stable vitals
 Anthropometry: Weight, Height; Assess standing and sitting
heights and calculate upper/lower segment ratio.
 Sexual Maturity Ratings (Tanner)
 Systemic Examination: Hepatosplenomegaly
3. Bone age assessment (X-ray of wrist and hand)
In cases with disproportionate SS- radiographs of tibia and spine
to exclude the presence of platylospondylosis or metaphyseal
cartilaginous dysplasia changes.
4. Co-morbidity screening: specially; hepatitis B, C, HIV.
5. Assess for other endocrinopathies: Serum free T4, TSH, fasting
glucose and oral glucose tolerance testing (OGTT) in case of
impaired fasting glucose (IFG), morning cortisol levels. The
HbA1c level is not reliable in screening for diabetes.
6. Biochemical investigations: Serum calcium, ionized calcium,
inorganic phosphate, magnesium, and alkaline phosphatase,
KFT, LFT.
7. Screening for Celiac Disease (in both boys and girls) using serum
tTG levels and Turner Syndrome (in girls).
8. Assessment of GH secretion is performed in cases with
height  - 3 SD and delayed bone age (described later).
9. LH, FSH, sex steroids (after 12e13 years if no clinical pubertal
development, any time thereafter in case of pubertal arrest).
2.4. Management
Key components of management of short stature in children
with TM include:
2.5. Assessment of GH secretion
i) Serum levels of IGF-1 and IGF BP-3 are estimated in children
with height  - 3 SD and delayed bone age (more than 2 SD or
delay > 2 years from chronological age). They are useful in-
dicators of growth hormone secretion and nutrition (low in
chronic liver disease and malnutrition) - Low levels indicate GH
deficiency or defect in IGF-1 generation.
ii) Growth hormone stimulation testing: Normal thyroid functions
are ensured before conducting the GH stimulation test. Peri-
pubertal children require priming with sex steroids before
evaluation by GH stimulation test. This is done for boys by giving
a single intramuscular injection of testosterone enanthate
100 mg seven days prior to testing and for girls by giving oral
ethinyl estradiol 50 mg for 3 days before testing. Another alter-
native regime that can be used in both boys and girls is conju-
gated estrogen 5 mg orally given night before and morning of
the test. Girls whose bone age is less than 9 years and boys
whose bone age is less than 10 years do not need priming [19].
Significant GH insufficiency may be diagnosed by a reduced
response of GH to two provocative tests (GH peak <10 ng/ml) in
children and adolescents or reduced response of GH in one test
plus low IGF-1 and IGF BP-3 concentrations [20].
MRI of the hypothalamic-pituitary region is useful to evaluate
pituitary iron overload as well as the size of pituitary gland
(atrophy).
2.5.1. Management
Treatment with recombinant human growth hormone (rhGH) is
indicated in cases with established GH deficiency. These subjects
often need higher doses due to co-existing partial GH insensitivity.
In children with pubertal delay best results are observed with
concomitant sex steroid replacement. Puberty induction with low
dose sex steroids may accelerate linear growth similar to the effect
of rhGH therapy [21]. The efficacy of rhGH treatment in the man-
agement of children with BTM having growth failure secondary to
Growth hormone deficiency has been a matter of debate. The linear
growth velocity attained after exogenous GH administration in
children with thalassemia is reported to be lower than that seen in
children with primary GH deficiency, possibly due to GH insensi-
tivity [22]. Since children with thalassemia have delayed bone age,
some improvement in linear growth is witnessed in the second
decade of life even without rhGH therapy. The current evidence

Table 3
Definitions in pubertal delay.

I. Delayed Puberty: Absence of gonadarche (Testicular Volume  4 ml) in males by 14 years and thelarche (appearance of breast bud) in females by 13 years.
II. Arrested puberty: Arrested puberty is defined as the absence of further pubertal progression once puberty has started for more than 1 year, where testicular volume in
boys never progressed beyond 6e8 ml and breast size in girls remained unchanged.
III. Primary amenorrhoea: Failure in menarche by 16 years.
IV. Secondary amenorrhoea: Absence of menstrual periods for >12 months after menarche.
 P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106
supports the short term use of rhGH therapy in thalassemia pa-
tients with short stature as it augments the linear growth velocity
with maximum benefit being observed in first year of therapy,
However, data to demonstrate its long term benefit in improving
final height is lacking [23,24]. There is uncertainty regarding the
ideal time to start GH therapy and the dosage. Finally, the decision
to use rhGH therapy should depend on the patient profile (age,
pubertal status), comorbidities (iron overload and chronic liver
disease), cost benefit ratio and the risk of adverse events (impaired
glucose tolerance). During GH treatment, patients should be
monitored at 3-monthly intervals with a clinical assessment and an
evaluation for parameters of GH response (growth parameters,
compliance) and adverse effects.
3. Pubertal disorders
The prevalence of pubertal disorders in adolescents with thal-
assemia despite regular transfusions and optimal chelation therapy
ranges between 30 and 70% in various studies [2]. Early recognition
and adequate management of such children can not only help in
optimizing growth and puberty but also improve the quality of life
and restore the fertility potential. The key factor implicated is the
iron overload that mediates its oxidative damage (through iron-
generated free radicals) to the hypothalamic- pituitary- gonadal
axis. The cause is usually damage to gonadotrophs in anterior pi-
tuitary leading to failure of adequate production of gonadotrophins
LH & FSH. Direct gonadal damage by iron overload is much less
likely. In fact, many patients have normal ovarian function and can
produce expected number of ova after stimulation and thus achieve
fertility.
The clinical presentation can range from a delay in the onset of
puberty to pubertal arrest and complete failure (Table 3). Presence
of pubertal abnormalities has many implications apart from po-
tential infertility. It contributes towards short stature due to absent/
poor pubertal growth spurt. Associated poor sexual development
contributes towards poor body image in the adolescent subject
with thalassemia. Since sex steroids have an important role to play
in pubertal bone mass accrual, these subjects fail to achieve opti-
mum bone mass, a factor that contributes towards osteopathy
observed thalassemia. The adolescent girls usually suffer from
primary amenorrhea while secondary amenorrhea likely to be
encountered in the older age group (late twenties). The uterus and
gonads show a subnormal growth and reach a final size smaller
than their age matched healthy cohorts. Similarly, the boys fail to
show the pubertal growth spurt, appearance/progression of sec-
ondary sexual characteristics and increase in the testicular volume.
MRI brain is a useful tool to assess the degree of siderosis in the
pituitary (reduced signal intensity in anterior pituitary) to provide
an insight to the disease progression and prognosis.
3.1. Assessment of delayed puberty in thalassemia
In thalassemia, a close clinical, biochemical and at times USG
monitoring is of utmost importance to determine any deviation
from the course of normal pubertal development. Besides a regular
growth monitoring, the progression of puberty is assessed by SMR
staging (Tanner staging) every six months starting from the age of
10 years. Girls without evidence of puberty by 13 years and boys by
14 years require further evaluation for delayed puberty. If bone age
for pubertal onset has been achieved (11 year in girls & 12 years in
boys), serum levels of LH, FSH, and estradiol/testosterone are esti-
mated to determine the functioning of the HPG axis. Low FSH and
LH for age indicate hypogonadotropic hypogonadism (HH) (hypo-
thalamic-pituitary lesion). In subjects with equivocal results, GnRH
analogue stimulation test (with Injection tryptorelin 0.1 mg/m2 S/C)
101
is needed for evaluating the pituitary ability to synthesize and
secrete gonadotropins. If LH and/or FSH are low (peak serum LH
level <5 IU/L after 4 h) after GnRH stimulation, it indicates that
pituitary is not yet primed to enter puberty, indicating delayed
puberty or possible hypogonadotrophic hypogonadism (HH).
Rarely, pubertal failure may be due to direct gonadal damage this
would be indicated by presence of elevated FSH and LH levels.
Bone age evaluation is useful for prediction of the remaining
growth potential and final adult height of these patients. Pelvic
ultrasound is useful in assessing ovarian and uterine maturation.
MRI pituitary (T2*) can be utilized as an early tool to detect iron
deposits in the pituitary.
3.2. Management
There are no standard recommendations to guide pubertal in-
duction in chronic diseases like thalassemia. The protocols used to
induce puberty in constitutional delay of puberty can be applied in
such cases with delayed puberty [19,25]. The primary goal in the
management of delayed puberty is to mimic biological and
biochemical pubertal events with concomitant promotion of sexual
maturation and linear growth. These goals can be achieved by
pubertal induction at a bone age of >11 years and >12 years for girls
and boys respectively; in adolescents with pubertal delay. It is
underscored that the children planning to go to TM who have
delayed puberty should not undergo pubertal induction as that
simply increases the risk of infertility.
The puberty induction should not be delayed beyond 14 years to
maximise growth potential and avoid deleterious effects on bone
mineral accrual. The optimal regime depends on the patient profile
age, height and expected height, financial condition, psychological
state, the set treatment goals and the personal experience of the
treating endocrinologist. Chatterjee et al. [26] reported successful
outcome of priming by low dose sex steroid in a small Indian
cohort. In a 6-year prospective study of 55 Indian TM children
(15e18 years) with stunted growth and delayed/arrested puberty,
80% reported favourable response to low dose sex steroid priming
(6e12 months) with increase in height, growth spurt and
completed pubertal maturation (Tanner stage 4e5) [26].
3.2.1. Boys
Boys are treated with a depot testosterone preparation @ 50 mg
i.m every 4 weeks for a duration of 6 months [19,25]. This leads to
an increase in penile size and the appearance of pubic hair. If during
this time an increase in testicular volume is observed, it indicates
activation of the H-P-G axis and release of gonadotrophins (FSH and
LH). In this situation, no further doses are given and children fol-
lowed closely for progression of spontaneous puberty.
3.2.2. Girls
Adolescent girls with pubertal delay are primed with a low dose
oral estrogen preparation. At our centre, we use ethinyl estradiol
(initial dose 2.5e5 mg/day) or estradiol valerate 0.5 mg/day for 6
months. During this time, they are followed for spontaneous pro-
gression indicated by breast development more than that expected
for the low dose of sex steroids given. In such girls, the therapy is
stopped after 6 months and follow up continued for spontaneous
pubertal induction [19,25].
Adolescents who do not sustain pubertal development after
withdrawal of sex steroids as given above are likely to have per-
manent hypogonadism and require induction of puberty using
exogenous Hormone Replacement Therapy or gonadotrophins
[19,25].
102 P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106
3.2.3. Pubertal induction in boys
In boys, therapy consists of gradually increasing doses of intra-
muscular depot preparations of testosterone enanthate starting
from 50 mg every 4 weeks, with progressive increase in the dose
every 6e12 months in increments of 50 mg until the adult
replacement dose is achieved (over a period of 3e4 years), which is
300 mg every 3 weeks In cases where testicular volume is pre/early
pubertal, the above therapy is combined with injection hCG @
500e1500 IU (s,c or i.m) on alternative days or a combination of
hCG and FSH (human menopausal gonadotropin, highly purified
urinary FSH or recombinant FSH), the latter @ 75e100 IU (s.c or i.m)
on alternate days. In this situation the therapy is initially started
with injection hCG; and FSH added after 6e12 months if the
testicular volume plateaus [25].
3.2.4. Pubertal induction in girls
For girls who do not show any response to the low dose estrogen
therapy after 6e12 months or in cases of ovarian failure, dose of
estrogen is gradually escalated (usually every 6e12 months) over a
period of 2e3 years, until a daily adult replacement dose is ach-
ieved. This corresponds to 0.6e1.25 mg conjugated equine oes-
trogen, 20 mg ethinylestradiol or 2 mg/day of estradiol valerate.
When menarche is achieved, or after 2 years of estrogen therapy, a
cyclic progestogen: medroxyprogesterone (5e10 mg/day) or nor-
ethisterone (0.7e1.0 mg/day) is added for 10e14 days every month,
with the objective of establishing regular monthly menstrual
cycles.
A similar hormone therapy is indicated in adolescents with
pubertal arrest after spontaneous onset of puberty or those who
seek care later during adolescence. In these adolescents, thera-
peutic regime is guided by the growth potential, clinical response
and emotional factors. It is seen that ovarian and testicular reserves
are usually preserved in HH patients, as they are still able to in-
crease estradiol or testosterone levels following gonadotrophin
stimulation test to produce ova or sperms in females and males,
respectively [27,28].
4. Impaired pancreatic b-cell function
The intensive management of thalassemia in children with
regular blood transfusions and chelation therapy has led to pro-
gressive decline in the prevalence of Impaired Glucose tolerance
(IGT) and Diabetes mellitus (DM) from 30 to 70% (early 90's) to
5e24% [29,30]. Like other endocrine complications, IGT and DM
usually develop in second decade of life or later. The prevalence of
DM and IGT in adolescents and young adults with thalassemia
conventionally treated with DFO varies in different series from 0 to
10.5% [2,31] and from 17 to 24%, respectively [29,32,33].
4.1. Mechanism of toxicity
The pathophysiology of impaired glucose homeostasis in b-
thalassemia is complex and multifactorial [34e39]. The key factors
responsible for the development of diabetes in thalassemia are iron
overload, chronic liver disease, viral hepatic infections (transfusion-
associated infections like Hepatitis C) and genotype of the indi-
vidual. A state of hyperinsulinemia secondary to iron overload
induced hepatic and pancreatic dysfunction is observed during the
second decade in thalassemia. Further, the secondary hemoside-
rosis in liver and muscles lead to peripheral Insulin resistance
possibly due to abnormalities of Insulin receptors or glucose
transporters. Gradually over time, impaired pancreatic b-cell
function results in progressive b-cell exhaustion culminating to
Insulin deficiency. Both Insulin resistance and deficiency, alone or
in combination lead to a state of impaired glucose tolerance (IGT)
and subsequently evolve to Type 1 Diabetes mellitus. The diabetes
in thalassemia differs from the classical Type 1 DM by the absence
of Islet cell antibodies, no relation with HLA DR/DR4 and infrequent
association with DKA [40]. However diabetics with thalassemia are
more predisposed to develop nephropathy (oxidative stress) [41]
and less likely to develop retinopathy (low IGF-1 levels) [42]. The
progression from IGT to DM is usually slow and can-not be pre-
dicted. In one of the prospective study, the progression from IGT to
DM was reported in 12.4% adolescent thalassemics over a period of
10 years [32]. Beside iron overload, chronic anaemia, Zinc defi-
ciency and increased collagen deposition (secondary to increased
activity of iron dependent protocollagen proline hydroxylase
enzyme) leading to disturbed microcirculation in the pancreas are
implicated in the development of diabetes in thalassemia.
4.2. Assessment of glucose homeostasis in thalassemia
Early recognition of problems due to impaired glucose homeo-
stasis is essential. Children with impaired glucose tolerance and
diabetes are identified using the recommendations given by
American Diabetes Association [43]. A fasting plasma glucose is
assessed annually beyond 10 years of age, OGTT being indicated in
patients with FPG >110 mg/dl. Continuous glucose monitoring
system (CGMS) has emerged as a promising and valid tool in
detecting early glucose derangements in children and adults with
thalassemia [44,45] and is considered to be more sensitive than
OGTT which may miss episodic hyperglycemia. The HbA1c levels
are unsuitable for monitoring the long-term glycaemic control in
thalassemia patients with diabetes, fructosamine may be used
instead [46].
Diabetes in thalassemia significantly increases the risk for car-
diac complications, heart failure, hyperkinetic arrhythmias and
myocardial fibrosis [47]. Combined intensive iron chelation therapy
with DFO and deferiprone (DFP) is associated with an improvement
in glucose intolerance, particularly in patients in early stages of
glucose intolerance [48]. However, it is less effective in preventing
insulin resistance and does not prevent the progression to type 1
DM in all patients [49].
4.3. Management
Regular screening of hepatitis associated infections and inten-
sive chelation therapy are important to prevent or delay the
development of diabetes in children with thalassemia. Dietary
modification (judicious selection of complex carbohydrate and
proteins with moderate restriction of fat) and exercise play a vital
role in the management of children with thalassemia and IGT
especially during the early stages. Evidence supports the use of the
oral biguanide (metformin), in addition to diet and exercise to delay
or prevent the progression to overt DM [50]. In addition, oral gli-
benclamide [51] and Acarbose [52] have shown a promising role in
achieving glycemic control especially in children with Insulin
resistance. The role of Insulin therapy comes into play when all the
other measures fail and Insulin deficiency develops.
5. Osteoporosis
Reduced bone mass, fractures and bone pain are the common
causes of morbidity and disability in children with thalassemia.
Despite intensive transfusion regimes and chelation, the prevalence
of osteopenia and osteoporosis is reported to be as high as 50%e
90% in various studies [53,54]. The pathogenesis of osteoporosis is
distinct from the development of bony deformities secondary to
ineffective erythropoiesis and progressive marrow expansion seen
in children receiving inadequate transfusions. The key factors
 P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106
implicated in osteoporosis are delayed puberty, diabetes, hypo-
thyroidism, hypoparathyroidism, GH-IGF-1 deficiency, and inef-
fective erythropoiesis with marrow expansion [55]. Expansion of
bone marrow leads to mechanical interruption in bone formation,
cortical thinning, and fragility. The above factors create an imbal-
ance in bone remodelling; they inhibit osteoblast activation and/or
increase osteoclast function, leading to bone loss and osteoporosis.
Chronic anaemia stimulates erythropoietin synthesis that results in
bone resorption through high RANKL levels. Iron overload in thal-
assemia patients impairs the osteoid maturation and mineraliza-
tion by incorporation of iron in the hydroxyapatite crystals thereby
reducing the tensile strength and resulting in focal osteomalacia.
The use of high dose DFO has been associated with bony de-
formities due to its adverse effects on the cartilage. Some studies
have suggested an important role of gene polymorphisms in the
development of poor bone mineral density, though their precise
role in thalassemia is still not clear. Malnutrition, lack of physical
activity, deficiency of vitamin C, D and calcium are other contrib-
utory factors in the development of osteoporosis. There is increased
risk of vitamin D deficiency in patients with thalassemia compared
to age matched controls [56]. Vitamin D sufficiency is critical for
optimal bone health, reducing the risk of fractures and improving
the myocardial function especially in cases with cardiac iron
overload [57,58].
5.1. Assessment
Assessment of the bone mineral content (BMC) and the areal
bone mineral density (aBMD) is done using Dual energy X-ray ab-
sorptiometry (DXA) despite its limitations in reporting and inter-
pretation in the pediatric population (before 20 years). The antero-
posterior lumbar spine (L1e4) and total body less head (TBLH) are
the preferred skeletal sites for measurement in most children. In
pediatric patients, BMC or aBMD values of < 2 SD are considered
as having low bone mass for age. The diagnosis of osteoporosis in
pediatrics is based upon vertebral fractures alone or low bone
density and multiple long bone fractures (two or more long bone
fractures by age the 10 years or three or more long bone fractures
before age 19 years) [55]. BMD interpretation is related to age (and
the height in short subjects) sex and pubertal status. A baseline
DXA evaluation should be done at 10e12 years for girls and boys
annually and every 2 years thereafter. Bone Densitometry should
always be a part of the comprehensive bone health screen, which
includes complete blood count, erythrocyte sedimentation rate,
serum calcium, phosphorus, alkaline phosphatase, intact PTH, total
25 hydroxy vitamin D, BUN, creatinine, and urinary calcium to
creatinine ratio.
5.2. Management
Prevention, early diagnosis and prompt management of low
bone mass are the corner stones of optimizing bone health in
thalassemia. Intensive transfusion and chelation regimes, adequate
calcium (500e1000 mg/day) intake in combination with vitamin D
supplements and good physical activity improve bone mineraliza-
tion and prevent bone loss. Vitamin D deficiency is actively looked
for and treated with supplements to ensure sufficiency in all cases
with thalassemia for optimizing bone health [59]. In addition,
treatment of other endocrinopathies (hypothyroidism, diabetes,
hypoparathyroidism) and puberty induction using sex steroids is
critical in achieving adequate bone mineral accretion in children
and adolescents with thalassemia. Recent studies have reported
role of bisphosphonates in the management of thalassemia chil-
dren with osteoporosis [60] but further studies are needed to clarify
their long-term benefits and side effects.
103
6. Hypoparathyroidism
The prevalence of hypoparathyroidism, observed usually during
the second decade or beyond, is reported to vary from 3.6% to 20%
[61]. Parathyroid dysfunction develops because of iron overload in
parathyroid cells and resultant tissue fibrosis. Increased bone
resorption in response to chronic anaemia and ineffective eryth-
ropoiesis can suppress the PTH secretion from parathyroid gland.
6.1. Assessment
Hypoparathyroidism (HPT) is detected either as part of routine
biochemical screening (low serum calcium and or high fasting
serum phosphate) or signs and symptoms of hypocalcaemia like
tetany, seizures, carpopedal spasm, laryngeal stridor or paraes-
thesia in the hands and feet. HPT is diagnosed on the basis of low
serum calcium along with high phosphorous (fasting), low/normal
PTH and low 1,25 (OH)2 D levels. The 24 h urinary calcium and
phosphorous levels are low in these cases. In late cases, intracranial
calcifications (basal ganglia, frontoparietal areas of brain, thalami,
and internal capsule) may be detected.
6.2. Management
Treatment of symptomatic hypocalcemia in HPT is done by us-
ing intravenous 10% calcium gluconate solution. In an asymptom-
atic child oral calcium supplements (1 g/day) in divided doses are
prescribed. This is combined with active vitamin D supplements
calcitriol @ 15e30 ng/kg/day (max 1.5 mg/day) to maintain the
serum calcium concentrations in low normal range [19]. Weekly
blood tests (serum calcium and phosphorous) are needed at the
start of therapy, followed by quarterly plasma and urinary calcium
and phosphorous measurements to monitor for hypercalciuria.
7. Adrenal functions
Children with thalassemia experience adrenal dysfunction
because of excessive iron deposits affecting the hypothalamic-
pituitary- adrenal axis at different levels. Clinically overt adrenal
insufficiency is uncommon in thalassemia. However, various
studies have reported presence of biochemical adrenal insuffi-
ciency in the range of 0e45% [61]. The variable prevalence can be
explained by the differences in the cut offs used for serum cortisol
and the degree of hemosiderosis. Adrenarche is usually delayed in
thalassemia patients, due to low adrenal androgen production. In
the subset with primary adrenal insufficiency, the cortisol, aldo-
sterone, and androgen secretion are impaired, each to a variable
extent, while secondary or tertiary adrenal insufficiency (pituitary
or hypothalamic affected) causes no mineralocorticoid defect [62].
The thalassemia patients with chronic liver disease often falsely
report low cortisol levels due to the low cortisol binding globulin
levels (CBG), synthesized in liver.
7.1. Assessment of adrenal functions
Adrenal function is assessed every 1e2 years beginning from the
age of 9 years, especially in children with growth hormone defi-
ciency receiving rhGH therapy. A morning cortisol levels (8 a.m.) is
done in all patients and values < 138 nmol/L are considered low. An
ACTH stimulation test with cortisol measured 60 min after an
intravenous injection of ACTH (Synacthen, 0.25 mg) detects sub-
clinical adrenal insufficiency as indicated by cortisol level of
<500 nmol/L (18 mg/dL) 60 min after ACTH administration.
104 P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106
Table 4
Protocol to screen endocrinopathies in children with TM.
Issues Assesment
Poor Growth Height and weight monitoring 6 monthly
Maintain a longitudinal record on a growth chart
Delayed/Arrested Puberty Biannual (every 6 months) assessment of growth (height, weight) and pubertal progress using SMR staging.
Impaired b cell function Annual Blood Glucose (fasting/post prandial); Oral Glucose tolerance test if clinically indicated
Osteoporosis Annual/Biennial DEXA
Hypoparathyroidism Serum Ca/PO4/ALP 6 monthly
Annual Vitamin 25 (OH)D and PTH
Hypothyroidism Annual FT4/TSH
Adrenal insufficiency Annual morning serum cortisol
7.2. Management
Under basal conditions, subclinical impairment of adrenocor-
tical function in patients with thalassemia is of not much clinical
significance. However, it has relevance during stressful situations
where in glucocorticoid supplementation may be indicated to
prevent adrenal crisis [63].
8. Hypothyroidism
The thyroid dysfunction in thalassemia develops as a result of
thyroidal cell siderosis, usually seen in the second decade of life.
Primary hypothyroidism occurs much before the iron toxicity af-
fects the hypothalamic-pituitary axis; making secondary hypothy-
roidism a much rarer entity. The prevalence of hypothyroidism
varies from 0 to 18% as demonstrated in various studies [3]. The
mechanisms of injury are possibly lipid peroxidation, free radical
release and oxidative stress due to iron overload. The degree of
thyroid dysfunction is directly related to the degree of iron over-
load, with the early stages being reversible by intensive chelation
therapy. However, the progression of subclinical to overt hypo-
thyroidism is not foreseeable and may take many years [64]. The
patients are usually asymptomatic and have an impalpable thyroid
gland. Studies have reported serum ferritin to positively correlate
with the TSH and USG of the thyroid gland (reduced echogenicity
with reduced volume and thickening of the thyroid capsule), and
predict the progression of the thyroid dysfunction in thalassemia
[65]. Apart from contributing towards statural growth and bone
mineralisation, optimising thyroid functions is important for
improving the cardiac function, since cardiac failure is the most
important cause of mortality in thalassemia.
8.1. Assessment of thyroid functions
It is recommended to have annual evaluation of thyroid function
tests beginning at the age of 10 years (unless symptomatic hypo-
thyroidism is present) [19]. Assessment of thyroid functions in-
volves measurement of serum T4 (free) and TSH levels. The patient
can have biochemical features of subclinical (low or normal free T4
with a high TSH) or overt hypothyroidism (low free T4 with a high
TSH).
8.2. Management
Good compliance with chelation therapy may prevent or reverse
thyroid dysfunction in early stages. Sub-clinical hypothyroidism-
basal TSH 5e7 mIU/ml will require regular follow-up and opti-
mizing chelation therapy [19]. Cases with overt hypothyroidism are
managed with age appropriate dose of L-thyroxine.
9. Annual endocrine screening
Since most endocrine complications make an appearance dur-
ing the second decade of life and beyond, it is recommended that all
children with TM undergo a comprehensive annual endocrine
screening beginning 9 years of age (Table 4) [19]. Prior to that, a
regular growth monitoring is done every 6 months from enrolment
and pubertal onset and progression are determined every 6 months
after the age of 10 years. The annual endocrine includes thyroid
function tests (free T4 and TSH), fasting glucose, oral glucose
tolerance test (if indicated), serum Calcium, serum phosphate
(fasting), vitamin D and PTH (if indicated by clinical symptoms or
biochemical features), and bone age. The LH, FSH, and sex steroids
are evaluated in the adolescents with delayed/arrested puberty. A
baseline DXA scan followed by annual/once in 2 years screening of
bone mineral density is also recommended.
10. Summary and conclusions
Management of a child with thalassemia requires regular eval-
uation by an endocrinologist beginning second decade of life due to
a high prevalence of endocrine dysfunctions seen in these patients.
Prevention is the best approach since efficacy of intensive chelation
in reversing established endocrinopathies is unknown. Thus, pre-
venting anaemia through a regular transfusion schedule, optimum
chelation, maintaining an adequate nutritional status and prompt
recognition and treatment of co-morbidities form the cornerstones
of endocrinopathy prevention. However, the endocrinopathies are
still being seen because the majority of TM patients lack adequate
clinical care. Early identification and prompt management of the
endocrine complications have a significant role in reducing
morbidity and mortality of thalassemia patients.
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