Open Journal of Endocrine and Metabolic Diseases, 2014, 4, 25-34

Published Online February 2014 (http://www.scirp.org/journal/ojemd)

http://dx.doi.org/10.4236/ojemd.2014.42003

A Review of Endocrine Disorders in Thalassaemia

Parijat De1, Radhika Mistry1, Christine Wright2, Shivan Pancham2,
Wyn Burbridge1, Kalyan Gangopadhayay1, Terence Pang1, Gautam Das3
1
Department of Diabetes, Endocrinology and Lipid Metabolism, City Hospital, Birmingham, UK
2
Sickle Cell and Thalassaemia Unit, City Hospital, Birmingham, UK
3
Department of Diabetes and Endocrinology, Southern General Hospital, Glasgow, UK
Email: p.de@nhs.net

Received November 4, 2013; revised December 4, 2013; accepted December 11, 2013

Copyright © 2014 Parijat De et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accordance of
the Creative Commons Attribution License all Copyrights © 2014 are reserved for SCIRP and the owner of the intellectual property
Parijat De et al. All Copyright © 2014 are guarded by law and by SCIRP as a guardian.

ABSTRACT
Endocrine dysfunction in thalassaemia is amongst the most common complication and is principally attributed
to excessive iron overload and suboptimal chelation. The prevalence is quite high particularly in multiethnic
populations but determining the prevalence is often difficult due to the widespread heterogeneity of the popula-
tion and timing of exposure to chelation therapy. Disturbances in growth, pubertal development, abnormal go-
nadal functions, impaired thyroid, parathyroid and adrenal functions, diabetes and disorderly bone growth are
commonly encountered. Early detection and institution of appropriate transfusion regimen and chelation thera-
py and treatment of complications are the keys to managing this population including regular follow. In this ar-
ticle, we review the literature in relation to the various endocrine complications encountered in thalassaemia.

KEYWORDS
Thalassaemia; Chelation; Endocrinopathies; Diabetes; Hypothyroidism

1. Introduction Thus, data regarding the prevalence of endocrine dys-

function in patients with ß thalassaemia major are limited
Thalassaemia major is a hereditary disorder of haemog-
and often depend on compliance with treatment [5-8].
lobin synthesis and the homozygous state results in se-
Massive iron deposition is caused by chronic anaemia
vere anaemia. Historically the homozygous condition
resulting in profound tissue hypoxia as well as compen-
was known to affect a significant population in Mediter-
satory responses, including increased bone marrow eryt-
ranean countries and the Middle East; however, migra-
hropoiesis and increased intestinal iron absorption. De-
tion has changed the geographic spread and made it a
spite the availability of chelation therapy, iron overload
worldwide health problem. The combination of transfu-
remains problematic because of poor acceptability of the
sion and chelation therapy has dramatically extended the
currently available agents, which require parenteral ad-
life expectancy of thalassaemic patients but is compli-
ministration and close blood monitoring. Disorders of
cated by citrate toxicity and subsequent iron overload
growth, sexual development & fertility, abnormal bone
resulting in a high incidence of endocrine abnormalities
mineralisation, diabetes mellitus, hypothyroidism and hy-
in children, adolescents and young adults [1]. Excessive
poadrenalism are the main endocrine complications found
iron is deposited in most tissues primarily in the liver,
in thalassaemic patients [9].
heart and the endocrine glands [2]. Bannerman et al. in
1967 published the first report of multiple endocrinopa-
thies [3]. Endocrinopathies are now amongst the com-
2. Growth in Thalassemia
mon complications of thalassaemia but determining the Thalassaemic children show retardation of growth in the
exact prevalence is difficult because of differences in age foetal, infantile, the pre-pubertal and the pubertal periods
of first exposure to chelation therapy and the continuing [9]. Approximately 20% - 30% of such patients have
improvement in survival in well-chelated patients [4]. growth hormone (GH) deficiency [10]; in the remaining

OPEN ACCESS OJEMD

26 P. DE ET AL.

70% - 80% provocative tests such as clonidine or gluca- couraging, the impact of treatment on final height of
gon stimulation tests have revealed a peak growth hor- non-GH deficient thalassaemic children remains uncer-
mone levels lower than those found in patients with con- tain [13] and often GH produces uncertain clinical re-
stitutional short stature. Potential causative factors for sponse [24,25]. Most patients lack the pubertal spurt and
growth failure include iron overload, free radical toxicity have reduced GH peak amplitude [26], hence responses
[11] desferrioxamine toxicity [12], zinc deficiency, to recombinant human GH therapy is poor when com-
anaemia, delayed puberty, primary hypothyroidism [13], pared with that of children with GH deficiency, idi-
liver cirrhosis and defect in the Growth Hormone-Insu- opathic short stature or Turner Syndrome.
lin-like Growth Factor-1 (GH-IGF-1) axis [14].
The anterior pituitary gland is particularly sensitive to 3. Hypogonadism and Puberty in
free radical oxidative stress. Magnetic resonance imaging Thalassaemia
(MRI) shows that even a modest amount of iron deposi-
Sexual immaturity is a profound complication of severe
tion within the anterior pituitary can interfere with its
thalassemia. Multiple gonadal and pituitary-gonadal
function [11]. Twenty-four hour profile of GH in thalas-
function studies have confirmed primary gonadal failure
saemic patients and GH response to GHRH is no differ-
due to gonadal iron deposition [27]. Secondary hypogo-
ent from that of idiopathic short stature children [15], but
nadism results from iron deposition on gonadotrophic
there may be an increased somatostatin tone, which in-
cells of the pituitary gland as shown by poor response of
terferes with the GH secretion [16].
FSH and LH to GnRH stimulation [28-30] or a combina-
Low serum IGF-1 and normal GH reserve in thalas-
tion of both primary and secondary hypogonadism [31].
saemic patients imply that a state of relative GH resis-
The incidence rate of failure of onset of puberty is 50%
tance exists and the rise in IGF-1 and improvement in
in some studies and may approach even 100% [9]. Evi-
growth with GH therapy suggest that the resistance is
dence suggests those with more severe defects have a
only partial at the post receptor level [13]. Moreover li-
greater rate of iron loading possibly due to increased
near growth in childhood is disrupted due to anaemia,
vulnerability to free radical toxicity. Iron toxicity on adi-
ineffective erythropoiesis, high ferritin levels & desfer-
pose tissue has also been shown to cause impaired syn-
rioxamine treatment. This is because desferrioxamine thesis of Leptin and consequently a delay in sexual ma-
and iron loading at the growth plate may have deleterious turation [32]. Leptin is a polypeptide hormone produced
effects on local IGF-1 production and paracrine growth by adipose cells due to expression of the ob gene and acts
regulation [12], hence early chelating agents inhibits cell as a permissive signal to initiate puberty. Gross iron
proliferation, protein synthesis and mineral deposition overload in the pituitary, hypothalamus and gonads is
lowering the activity of alkaline phosphatase. Abnormal progressive even with chelation therapy [33]. Patients
body proportions with truncal shortening are commonly with low gonadotropin levels have significant unrespon-
seen and could be due to the disease itself, iron toxicity siveness to gonadotropin releasing hormone compatible
and toxic effects of desferrioxamine [13]. with a hypothalamic and pituitary damage [34]. Delayed
Karamifar et al. [17] have demonstrated that 62.9% of onset of menarche, oligomenorrhoea, secondary amen-
girls and 69% of boys affected with thalassaemia were norhoea, attenuated testicular size (of 6 - 8 ml) and breast
less than 2SD below the mean for normal height. Roth et size at Tanner Stage 2 or 3 are common manifestations of
al. [18] showed that 40.6% of patients were short in sta- significantly elevated serum iron and ferritin levels [5,
ture (height below third percentile). Similarly Soliman et 35].
al. [19] reported a prevalence of short stature (<2SD) in The yearly growth velocity in thalassaemic patients is
49% of their thalassemic patients. Moayeri et al. [20] either markedly reduced or completely absent [35]. Up to
showed that 62% were less than 2SD and 49% were 3SD 20% of such patients have short stature [10] and the ab-
below the mean and also confirmed decreased growth sence of pubertal growth spurt during spontaneous or
hormone response to two provocative tests and low le- induced puberty is detrimental to the achievement of a
vels of IGF-1 in a majority of their thalassaemic patients. normal final height [13]. Disproportionate body propor-
Moreover Gulati et al. [21] and Theodoridis et al. [10] tions and changes in spinal growth [36] further impair
have also reported similar reduced responses to provoca- truncal growth.
tive tests in 51% and 20% of thalassaemic patients re- Chern et al. [37] have demonstrated a high prevalence
spectively. Borgna-Pignatti et al. [22] have also con- of hypogonadotropic hypogonadism in their study sub-
firmed short stature in 40.6% of their thalassaemic sub- jects. The overall prevalence was 72%, with 45% preva-
jects. A more recent study by Vogiatzi et al. has shown lence in boys and 39% in girls. Considerable delay or
that 25% of the 361 subjects regardless of the thalassae- arrest in development of secondary sexual characters and
mia syndrome had short stature. [23] menstrual cycle was also noted. Similar results of de-
Although the results of short term GH therapy are en- creased gonadal function were also noted in 75% girls

OPEN ACCESS OJEMD

 P. DE ET AL. 27

and 62% boys in a cross sectional study conducted at al. [47] showed IGT in 10.8% of their study subjects. A
Hong Kong [38]. multicentre study in Cyprus [48] showed that 9.4% of
Moayeri et al. [20] reported puberty failure in 69% of thalassaemic patients had diabetes. Najafipour et al. [49]
thalassaemic patients with low levels of FSH and LH have shown the prevalence rates of diabetes mellitus,
(73.2% in males and 64.8% in females) and their results impaired fasting glucose and impaired glucose tolerance
were consistently similar to the multicentre study that in their group of thalassaemic patients to be 8.9%, 28.6%
was being conducted at Italy [35], which showed hypo- and 7.1% respectively. Overall prevalence ranges from
gonadism in 47% females and 51% males. Soliman et al. 6.4% to 14.1%. The development of glucose intolerance
[19] have also reported lack of puberty in 73% males and is progressive; this is related to poor compliance with
42% in thalassaemic patients with age less than 21 yrs. chelation therapy and presence of hepatic fibrosis or
Moreover Borgna-Pignatti [22] and colleagues have also cirrhosis. Guidelines recommend screening with the oral
reported puberty failure in 67% males and in 38% fe- glucose tolerance test (OGTT) and studies have shown
males respectively. Notably, women who are well che- those with higher responses are more likely to have dete-
lated may still conceive successfully. riorating glucose tolerance [50,51]. However OGTT
Chelation therapy initiated early prior to the onset of compliance is often poor. Pancreatic iron overload can be
adrenarche and administration of low dose sex steroids assessed my MRI [52] but doesn’t seem to correlate with
during adolescence may promote growth of bones, siderosis in other organs.
growth velocity and sexual maturation [9]. Chatterjee et Although inadequate insulin release has been reported
al. 2011 [39] have since confirmed feasibility for low by several groups [42,53,54], hyperinsulinaemia and de-
dose sex steroid priming in their Indian cohort as 80% creased insulin sensitivity [55] with reduced hepatic re-
reached pubertal maturation which was most effective in lease of insulin [9] has been presumed to be the main
younger patients with minimal iron overload. pathogenic mechanism. Siklar et al. [56] propose im-
paired insulin secretion precedes development of insulin
4. Glucose Intolerance and Diabetes Mellitus resistance. Moreover selective oxidative damage to pan-
creatic beta cells may also occur as a result of autoim-
Effective management of patients suffering from homo-
munity [56]. Beta cell function remains normal until the
zygous beta thalassaemia has led to improved life expec-
later stages of disease [9] but insulin sensitivity corre-
tancy and hence manifestations of haemosiderosis related
lates inversely with iron overload and age [57]. Fasting
complications, notably, disturbances of the exocrine and
pro-insulin and pro-insulin to insulin ratio is significantly
endocrine function of the pancreas [40]. But unlike hae-
increased and correlate positively with hepatic iron [58]
mochromatosis, where the incidence of diabetes is as
but C-peptide levels are variable indicating variable beta
high as 80% [41], the incidence is lower in thalassaemics
cell function [59,60]. Evaluation of exocrine function of
due to better diagnosis and treatment of the condition [9].
the pancreas shows decreased serum trypsin and lipase
Four out of eight patients of Lassman et al. [42] had di-
levels [61] with normal activity of alpha amylase. The
abetes. 50% of twenty patients studied by Suadek et al.
onset of diabetes mellitus tends to follow the develop-
[43] had abnormal glucose tolerance. Sixteen of eighty
ment of other endocrine and cardiac complications [62].
two patients interviewed by Chern et al. had diabetes and
Glucose intolerance correlates with at least 50% decline
risk was increased by co-infection with hepatitis C [44].
in beta cell function which is not entirely reversible even
Gamberini et al. [44] followed up 273 thalassaemic pa-
after intensive iron chelation but paradoxically, high
tients over a period of thirty years and have shown that
transfusion regime not accompanied by effective iron
42 patients developed insulin dependent diabetes mellitus.
chelation can increase the incidence of diabetes mellitus
They demonstrated that prevalence progressively in-
further.
creased with time. Noetzil et al. [45] found almost 50%
of patients studied had confirmed diabetes or abnormal
glucose tolerance and that pancreatic iron was the
5. Thyroid Dysfunction
strongest predictor of beta cell toxicity. The main risk Thyroid dysfunction is a frequently occurring endocrine
factors were poor compliance with desferrioxamine treat- complication in thalassaemia major, but its prevalence
ment (p < 0.05), advanced age at the start of intensive and severity is variable and the natural history is poorly
chelation therapy, liver cirrhosis or severe fibrosis. Pre- described [63]. Autoimmunity has no role in the patho-
valence of impaired glucose tolerance (IGT) was also genesis of thalassaemia related hypothyroidism [64]. Up
high and was associated with male sex, poor compliance to 5% of thalassaemic patients develop overt clinical
with desferrioxamine therapy and a very high liver iron hypothyroidism that require treatment [35] whereas a
concentration. The Italian working group [46] demon- much greater percentage have sub-clinical compensated
strated diabetes in 4.9% of patients whereas Aydinok et hypothyroidism with normal T4 and T3 but high TSH

OPEN ACCESS OJEMD

28 P. DE ET AL.

levels. It usually occurs in severely anaemic and/or iron It is questionable as to what action should be taken in
overload thalassaemics but is uncommon in optimally mild hypothyroidism. De Sanctis et al. [78] showed that
treated patients [7,65]. The pathogenesis is again unclear good compliance with chelation therapy appeared to im-
but thought to relate to lipid perioxdiation, free radical prove thyroid function and routine surveillance for hy-
release and oxidative stress [65]. The incidence of hypo- pothyroidism is unnecessary in thalassaemia major [79].
thyroidism is directly related to the degree of iron over-
load and most patients have ferritin levels close to 2000 6. Hypoparathyroidism
µg/l. Typically the thyroid gland is impalpable, thyroid
Hypocalcaemia due to hypoparathyroidism is a recog-
antibodies are negative and often clinical features of the
nized late and rare complication principally due to iron
disease are absent. Thyroxine levels have been reported
overload. It has a higher incidence in males and usually
normal in majority of patients [5,27,31,66] suggesting
evident after 10 years of age [35]. The loss of diurnal
insensitivity of the thyroid gland to iron overload. How-
variation in parathyroid hormone (PTH) levels is the first
ever low or normal T4 values with elevated TSH have
evidence [9]; patients typically have low calcium, PTH &
been also reported suggesting sub-clinical primary hypo-
Vitamin D levels and high phosphate levels. Zamboni et
thyroidism [5,31,67,68]. An exaggerated TSH response
al. [80] demonstrated decreased PTH levels and sub-
to stimulation by thyrotrophin-releasing-hormone (TRH)
sequently impaired vitamin D synthesis in their older
was found by De Sanctis et al. [69] in 8 of 24 thalassae-
thalassaemic patients. The manifestations are primarily
mics studied and a third of those went on to develop sub-
noted in the second decade. Iron toxicity may cause overt
clinical or overt hypothyroidism three to eleven years
hypoparathyroidism in 3% - 4% of thalassaemia patients
later. This suggests the development of thyroid disease
whereas preclinical hypoparathyroidism was recently
may have a fairly protracted course. De Sanctis et al. [69]
reported to occur in close to 100% of thalassaemic pa-
reported predominance of the mildest form of primary
tients [81]. Angelopoulos et al. [82] in their study of
hypothyroidism in their cohort of 97 patients with tha-
transfusion dependant patients with β thalassaemia have
lassaemia where the disease course was mostly stable.
demonstrated hypoparathyroidism in 13.5% subjects with
Thyroid ultrasonography usually shows reduced echoge-
significant low levels of intact parathyroid hormone and
nicity of the gland due to reduced volume with thicken-
total and ionized calcium. Similarly Aleem et al. [83]
ing of thyroid capsule. Chirico et al. [70] followed up 72
have shown that 20% of their patients had hypoparathy-
thalassaemic patients over a period of eight years and
roidism which was much higher compared to the multi-
demonstrated ferritin levels correlate positively with both
centre study in Italy [35] involving 25 centres which
TSH and thyroid volume on ultrasonography and can
showed the prevalence to be 3.6%. A French study from
predict progression of thyroid disease. This is contrary to
1993 showed the prevalence to be as high as 22.5% [84].
previous studies [71,72] including a 12-year longitudinal
Shamshirsaz et al. [1] in their multicentre study in Te-
study by Filosa et al. [72] 7 years earlier which showed
hran have shown a prevalence of 7.6%, which was higher
no association between ferritin levels or transfusion sta-
than the 3.6% - 7%, reported by other workers [8,35,85]
tuswith worsening thyroid function.
and the male: female ratio was 4:1, which was higher
Some studies have reported a high prevalence of pri-
than several other reports [35,86].
mary hypothyroidism reaching up to 17% - 18% [7,73]
Limited data [87,88] shows that early supplementation
whereas others have reported a low prevalence of 0% -
with Vitamin D or calcitriol treatment for three months is
9% [74,75]. Shamshirsaz et al. [1] demonstrated a pre-
sufficient to normalize plasma calcium and phosphate
valence of 7.7% in their study similar to the Italian study
levels. Tetany, seizures or cardiac failure due to severe
group [35] who found 6.2% patients to be hypothyroid
hypocalcaemia is rare and requires immediate correction
where as Aydinok et al. [47] showed the prevalence to be
with intravenous administration of calcium.
higher at 16%. A more recent study by Toumba et al. [48]
showed that the prevalence of acquired hypothyroidism
was 5.9% which was consistent with other studies.
7. Adrenal Function
Investigation of thyroid function should be performed Histological and imaging studies have shown that iron
annually beginning at the age of 12 years. Elevated levels deposits in the adrenal cortex of thalassaemic patients are
of TSH and reduction in T4 and T3 result from increased mainly confined to the zona glomerulosa with rare in-
sensitivity of the gland to pharmacological doses of volvement of the zana fascicularis [89]. Most studies
Iodine [76] which may result in rapid progression of sub- have revealed intact pituitary adrenal axis in thalassae-
clinical hypothyroidism into a severe disease [77]. This is mics [27,31,53,54,66]. Prevalence of adrenal insuffi-
more detrimental in those with concomitant cardiomyo- ciency is variable and depends both on the degree of iron
pathy and thus caution is required with co-prescription of overload and cut off values for cortisol measurement.
Iodine based anti-arrhythmic agents such as amiodarone. McIntosh [54] found raised ACTH levels suggesting

OPEN ACCESS OJEMD

 P. DE ET AL. 29

primary adrenal failure, but Costin et al. [5] found re- performed by Vogiatzi et al. [101] showed that amongst
duced ACTH and adrenal reserve even in the absence of the 31 patients studied (26 major and 5 intermedia),
clinical signs. To support this finding baseline serum and 22.6% had reduced bone mass (Z = −1 to –2) and 61.3%
urinary cortisol levels are frequently normal which may had low bone mass (Z </= −2).
reflect reduced ability of the adrenal cortex to respond to Diagnosis is established early by BMD measurements
additional pulses of ACTH [90]. Patients usually have using various densitometry modalities. Prevention, early
dissociation between androgen, cortisol and aldosterone diagnosis and effective chelation therapy is most effec-
synthesis leading to low serum Dihydroepiandrostene- tive in arresting the progression of the disease. Diet rich
dione (DHEA), Dihydroepiandrostenedione Sulphate in calcium and Vitamin D and exercise can improve the
(DHEAS), androstenedione and testosterone levels, outcome [57]. Patients with hypogonadism should be
which also explains absence of adrenarche in these pa- treated with hormone replacement therapy.
tients [91]. Patients usually demonstrate an intact secre-
tory pattern of cortisol and aldosterone but abnormal cir- 9. Conclusion
cadian patterns of ACTH secretion [92]. Also, thalas-
Thalassemia patients have a high prevalence of endocri-
saemics with chronic liver disease may have falsely low
nological abnormalities. Several studies at different cen-
serum cortisol levels as it is normally bound to cortisol
tres have demonstrated the increased prevalence of en-
binding globulin (CBG) which is synthesised by hepato-
docrinopathies in patients with thalassaemia. Regular
cytes [93]. To date CBG level in thalassaemics hasn’t
follow-up is essential for the early detection and appro-
been reported, however, a normal level in the presence of
priate treatment of associated complications. Improve-
low cortisol excludes its role in adrenal insufficiency.
ments in protocols of transfusion regime and chelating
Inaccurate cortisol levels in women may be a reflection
therapy should hopefully improve the care and quality of
of oestrogen induced elevation in CBG levels. Imaging
life of these patients. Increasing awareness of endocrino-
studies using MR have frequently identified adrenal hy-
logical problems in thalassemic patients is essential not
pointensity without alteration of morphology in thalas-
only because such patients are living longer now, but
saemia patients and verified autopsy findings of correla-
also because much of the morbidity and mortality from
tion between adrenal iron and liver iron [94]. However,
these complications can be reduced with regular surveil-
despite high sensitivity, histology still remains the gold
lance, early treatment and follow-up in a multi-discip-
standard for diagnosis of iron deposition.
linary setting.
8. Osteoporosis
Beta thalassemia is associated with marrow expansion,
REFERENCES
osteopaenia with cortical thickening, trabecular coarsen- [1] A. A. Shamshirsaz, M. R. Bekheirnia, M. Kamgar, N.
ing and bone deformity [95]. Factors implicated in its Pourzahedgilani, N. Bouzari, M. Habibzadeh, R. Hashemi,
A. A. Shamshirsaz, S. Aghakhani, H. Homayoun and B.
cause include hypogonadism, diabetes mellitus, hypo-
Larijani, “Metabolic and Endocrinologic Complications
thyroidism, hypoparathyroidism, iron overload and its in Beta Thalassemia Major: A Muticentre Study in Te-
treatment [96]. Malnutrition, inadequate exercise and hran,” BMC Endocrine Disorders, Vol. 3, No. 1, 2003, p.
absence of adrenal sex hormones during adrenarche and 4. http://dx.doi.org/10.1186/1472-6823-3-4
gonadal hormones during puberty are other contributory [2] A. H. Al-Elq and H. H. Al Sayeed, “Endocrinopathies in
factors [97]. There is a high incidence of osteoporosis of Patients with Thalassemia,” Saudi Medical Journal, Vol.
the spine and hip in both sexes. In men the lumbar verte- 25, No. 10, 2004, pp. 1347-1351.
brae and femoral neck are affected while in women it is [3] R. M. Bannerman, “Thalassemia Intermedia, with Iron
the spine [96]. Due to significant reduction in cortical Overload, Cardiac Failure, Diabetes Mellitus, Hypopitui-
and trabecular bone mineral density, pathological frac- tarism and Porphyrinuria,” American Journal of Medicine,
tures are commonly encountered in more than 20% of Vol. 42, No. 3, 1967, pp. 476-486.
http://dx.doi.org/10.1016/0002-9343(67)90276-8
cases [98].
A multi centre study group in Tehran [1] demonstrated [4] N. Cappellini, A. Cohen, A. Eleftheriou, A. Piga and J.
Porter, “Guidelines for the Clinical Management of Tha-
that the prevalence of osteoporosis and osteopaenia in the lassemia,” Thalassemia International Federation, Strovo-
lumbar region (L1 - L4) region were 50.7% and 39.4% los, 2000, pp. 41-49.
respectively; the prevalence was 10.8% and 36.9% re- [5] G. Costin, M. Kogut, C. B. Hyman and J. Ortega, “Endo-
spectively in the femoral neck region. Similar results crine Abnormalities in Thalassaemia Major,” American
from other studies have also been reported [99,100]. Journal of Diseases in Children, Vol. 133, No. 5, 1979,
Jensen et al. [96] showed that the overall prevalence of pp. 497-502.
“severely low” bone mass was 51%; the prevalence of http://dx.doi.org/10.1001/archpedi.1979.02130050041009
“low” bone mass to be 45%. Further studies like one [6] M. Brezis, O. Shalev, B. Leibel, J. Berheim and D. Ben

OPEN ACCESS OJEMD

30 P. DE ET AL.

Ishay, “Phosphorus Retention and Hypoparathyroidism Lakomek and W. Schroter, “Short Stature and Failure of
Associated with Transfusional Iron Overload in Thalas- Pubertal Development in Thalassemia Major: Evidence of
semia,” Mineral Electrolyte Metabolism, Vol. 4, 1980, pp. Hypothalamic Neurosecretory Dysfunction of Growth Hor-
57-61. mone Secretion and Defective Pituitary Gonadotropin
[7] A. Sabato, V. De Sanctis, G. Atti, L. Capra, B. Bagni and Secretion,” European Journal of Pediatrics, Vol. 156, No.
C. Vullo, “Primary Hypothyroidism and the Low T3 Syn- 10, 1997, pp. 777-783.
drome in Thalassemia Major,” Archives of Diseases in http://dx.doi.org/10.1007/s004310050711
Childhood, Vol. 58, No. 2, 1983, pp. 120-127. [19] A. T. Soliman, M. Elzalabany, M. Amer and A. M. An-
http://dx.doi.org/10.1136/adc.58.2.120 sari, “Growth and Pubertal Development in Transfusion
[8] V. De Sanctis, C. Vullo, M. Katz, B. Wonke, A. V. Hoff- Dependant Children and Adolescents with Thalassemia
brand, A. Di Palma and B. Bagni, “Endocrine Complica- Major and Sickle Cell Disease: A Comparative Study,”
tions in Thalassemia Major,” In: C. D. Buckner, R. P. Journal of Tropical Pediatrics, Vol. 45, No. 1, 1999, pp.
Gale and G. Lucarelli, Eds., Advances and Controversies 23-30. http://dx.doi.org/10.1093/tropej/45.1.23
in Thalassemia Therapy, Alan Liss, New York, 1989, pp. [20] H. Moayeri and Z. Oloomi, “Prevalence of Growth and
77-83. Puberty Failure with Respect to Growth Hormone and Go-
[9] D. Tiosano and Z. Hochberg, “Endocrine Complications nadotropins Secretion in Beta Thalassemia Major,” Ar-
of Thalassaemia,” Journal of Endocrinological Investiga- chives of Iranian Medicine, Vol. 9, No. 4, 2006, pp. 329-
tion, Vol. 24, 2001, pp. 716-723. 334.
[10] C. Theodoridis, V. Ladis, A. Papatheodorou, H. Berdousi, [21] R. Gulati, V. Bhatia and S. S. Agarwal, “Early Onset of
F. Palamidou, C. Evagelopoulou, K. Athanassaki, O. Kon- Endocrine Abnormalities in Beta-Thalassemia Major in a
stantoura and C. Kattamis, “Growth and Management of Developing Country,” Journal of Pediatric Endocrinol-
Short Stature in Thalassemia Major,” Journal of Pediatric ogy and Metabolism, Vol. 13, No. 6, 2000, pp. 651-656.
Endocrinology and Metabolism, Vol. 11, Suppl. 3, 1998, http://dx.doi.org/10.1515/JPEM.2000.13.6.651
pp. 835-844. [22] C. Borgna-Pignatti, P. De Stefano, L. Zonta, C. Vullo, V.
[11] V. De Sanctis, “Growth and Puberty and Its Management De Sanctis, C. Melevendi, A. Naselli, G. Masera, S. Ter-
in Thalassemia,” Hormone Research, Vol. 58, Suppl. 1, zoli and V. Gabutti, “Growth and Sexual Maturation in
2002, pp. 72-79. http://dx.doi.org/10.1159/000064766 Thalassaemia Major,” Journal of Pediatrics, Vol. 106, No.
1, 1985, pp. 150-155.
[12] G. Raiola, M. C. Gallati, V. De Sanctis, M. Caruso Nicoletti, http://dx.doi.org/10.1016/S0022-3476(85)80488-1
C. Pintor, V. M. Arcuri and C. Anastasi, “Growth and
Puberty in Thalassemia Major,” Journal of Pediatric En- [23] M. G. Vogiatzi, E. A. Macklin, F. L. Trachtenberg, E. B.
docrinology and Metabolism, Vol. 16, Suppl. 2, 2003, pp. Fung, A. M. Cheung, E. Vichinsky, N. Olivieri, M.Kirby,
259-266. J. L. Kwiatkowski, M. Cunningham, I. A. Holm, M.
Fleisher, R. W. Grady, C. M. Peterson, P. J. Giardina and
[13] L. C. Low, “Growth, Puberty and Endocrine Function in Thalassemia Clinical Research Network, “Differences in
Beta Thalassemia Major,” Journal of Pediatric Endocri- the Prevalence of Growth, Endocrine and Vitamin D Ab-
nology and Metabolism, Vol. 10, No. 2, 1977, pp. 175- normalities among the Various Thalassaemia Syndromes
184. in North America,” British Journal of Haematology, Vol.
[14] E. Y. Kwan, A. C. Lee, A. M. Li, S. C. Tan, C. F. Chan, 146, No. 5, pp. 546-556.
Y. L. Lau and L. C. Low, “A Cross Sectional Study of [24] R. S. Britton, G. A. Ramm, J. Olynyk, R. Singh, R.
Growth, Puberty and Endocrine Function in Patients of O’Neill and B. R. Bacon, “Pathophysiology of Iron Tox-
Thalassemia Major in Hong Kong,” Journal of Paediat- icity,” Advances in Experimental Medicine and Biology,
rics and Child Health, Vol. 31, No. 2, 1995, pp. 83-87.
Vol. 356, 1994, pp. 239-253.
http://dx.doi.org/10.1111/j.1440-1754.1995.tb00752.x
http://dx.doi.org/10.1007/978-1-4615-2554-7_26
[15] L. Leger, R. Girot, H. Crosnier, M. C. Postel Vinay and R.
[25] N. Bridge, “Disorders of Puberty: Pubertal Delay and Pu-
Rappaport, “Normal Growth Hormone Response to GH
bertal Failure,” In: C. G. D. Brook and P. C. Hindmarsh,
Releasing Hormone in Children with Thalassemia Major
before Puberty: A Possible Age Related Effect,” The Journal Eds., Clinical Pediatric Endocrinology, 4th Edition, Black-
of Clinical Endocrinology & Metabolism, Vol. 69, No. 2, well Science, London, 2001, pp. 173-175.
1989, pp. 453-456. [26] N. Shehadeh, A. Hazani, M. C. Rudolf, I. Peleg, A.
http://dx.doi.org/10.1210/jcem-69-2-453 Benderly and Z. Hochberg, “Neurosecretory Dysfunction
[16] G. De Luca, M. Maggiolini, M. Bria, M. Caracciolo, A. of Growth Hormone Secretion in Thalassemia Major,”
Giomo, M. Salemo, S. Marsico, M. Lanzino, C. Brancati Acta Paediatrica Scandinavica, Vol. 79, No. 8-9, 1990,
and S. Ando, “GH Secretion in Thalassemia Patients with pp. 790-795.
Short Stature,” Hormone Research, Vol. 44, No. 4, 1995, http://dx.doi.org/10.1111/j.1651-2227.1990.tb11556.x
pp. 158-163. http://dx.doi.org/10.1159/000184617 [27] B. Kuo, E. Zaino and M. S. Roginsky, “Endocrine Func-
[17] H. Karamifar, M. Shahriari and G. H. Amirhakimi, “Fail- tion in Thalassemia Major,” Journal of Clinical Endocri-
ure of Puberty and Linear Growth in Beta Thalassemia nology and Metabolism, Vol. 28, No. 6, 1969, pp. 805-
Major,” Turkish Journal of Hematology, Vol. 22, No. 2, 808. http://dx.doi.org/10.1210/jcem-28-6-805
2005, pp. 65-69. [28] C. H. Anoussakis, D. Alexiou, D. Abatzis and G. Be-
[18] C. Roth, R. A. Pekrun, M. Bartz, H. Jarry, S. Eber, M. chrakis, “Endocrinological Investigation of Pituitary Go-

OPEN ACCESS OJEMD

 P. DE ET AL. 31

nadal Axis in Thalassemia Major,” Acta Paediatrica Scan- Bajoria, “Sex Steroid Priming for Induction of Puberty in
dinavia, Vol. 66, No. 1, 1977, pp. 49-51. Thalassemia Patients with Pulsatile Reversible Hypogo-
http://dx.doi.org/10.1111/j.1651-2227.1977.tb07806.x nadotrophic Hypogonadism,” Hemoglobin, Vol. 35, No.
[29] H. Landau, I. M. Spitz, G. Civadilli and E. A. Rachmilewitz, 5-6, 2011, pp. 659-664.
“Gonadotropin, Thyrotropin and Prolactin Reserve in Beta http://dx.doi.org/10.3109/03630269.2011.630121
Thalassemia,” Clinical Endocrinology, Vol. 9, 1978, pp. [40] E. Karahanyan, A. Stoyanova, I. Moumdzhiev and I. Ivanov,
163-173. “Secondary Diabetes in Children with Thalassemia Major
[30] O. A. Kletzky, G. Cossin, R. P. Marrs, G. Bernstein, C. M. (Homozygous Thalassemia),” Folia Medica (Plovdiv), Vol.
March and D. R. Mishell Jr, “Gonadotropin Insufficiency 36, No. 1, 1994, pp. 29-34.
in Patients with Thalassemia Major,” Journal of Clinical [41] S. C. Finch and C. A. Finch, “Idiopathic Hemochromatosis:
Endocrinology and Metabolism, Vol. 48, No. 6, 1979, pp. An Iron Storage Disease,” Medicine, Vol. 34, No. 4, 1955,
901-905. http://dx.doi.org/10.1210/jcem-48-6-901 pp. 381-430.
[31] M. N. Lassman, R. T. O’Brien, H. A. Pearson, J. K. Wise, http://dx.doi.org/10.1097/00005792-195512000-00001
R. K. Donabedian and P. Felia, “Endocrine Evaluation in [42] M. N. Lassman, M. Genel, J. K. Wise, R. Hendler and P.
Thalassemia Major,” Annals of the New York Academy of Felig, “Carbohydrate Homeostasis and Pancreatic Islet
Sciences, Vol. 232, 1974, pp. 226-237. Cell Function in Thalassemia,” Annals of Internal Medi-
http://dx.doi.org/10.1111/j.1749-6632.1974.tb20589.x cine, Vol. 80, No. 1, 1974, pp. 65-69.
[32] G. R. Moshtaghi-Kashanian and F. Razavi, “Ghrelin and http://dx.doi.org/10.7326/0003-4819-80-1-65
Leptin Levels in Relation to Puberty and Reproductive [43] C. D. Saudek, R. M. Hemm and C. M. Peterson, “Abnormal
Function in Patients with Beta-Thalassemia,” Hormones Glucose Tolerance in Beta Thalassaemia Major,” Metabo-
(Athens), Vol. 8, 2009, pp. 207-213. lism, Vol. 26, No. 1, 1977, pp. 43-52.
[33] R. Chatterjee, M. Katz, T. F. Cox and J. B. Porter, “Pro- http://dx.doi.org/10.1016/0026-0495(77)90126-3
spective Study of the Hypothalamic Pituitary Axis in the [44] J. P. Chern, K. H. Lin, M. Y. Lu, D. T. Lin, K. S. Lin, J.
Thalassemic Patients Who Developed Secondary Amenor- D. Chen and C. C. Fu, “Abnormal Glucose Tolerance in
rhea,” Clinical Endocrinology, Vol. 39, 1993, pp. 287- Transfusion Dependent β-Thalassemic Patients,” Diabetes
296. Care, Vol. 24, No. 5, 2001, pp. 850-854.
[34] L. Danesi, M. Scacchi, M. De Martin, A. Dubini, P. Mas- http://dx.doi.org/10.2337/diacare.24.5.850
saro, A. T. Majolo, F. Cavagini and E. E. Polli, “Evalua- [45] M. R. Gamberini, M. Fortini, V. De Sanctis, G. Gilli and
tion of Hypothalamic—Pituitary Function in Patients with M. R. Testa, “Diabetes Mellitus and Impaired Glucose
Thalassemia Major,” Journal of Endocrinological Inves- Tolerance in Thalassemia Major: Incidence, Prevalence,
tigation, Vol. 15, No. 3, 1992, pp. 177-184. Risk Factors and Survival in Patients Followed in the
[35] Italian Working Group on Endocrine Complications in Ferrara Centre,” Pediatric Endocrinology Reviews, Vol. 2,
Non-Endocrine Disease, “Multicentre Study on Preva- Suppl. 2, 2004, pp. 285-291.
lence of Endocrine Complications in Thalassemia Major,” [46] L. J. Noetzli, S. D. Mittelman, R. M. Watanabe, T. D. Coa-
Clinical Endocrinology (Oxf), Vol. 42, No. 6, 1995, pp. tes and J. C. Wood, “Pancreatic Iron and Glucose Dysre-
581-586. gulation in Thalassemia Major,” American Journal of He-
http://dx.doi.org/10.1111/j.1365-2265.1995.tb02683.x matology, Vol. 87, No. 2, 2012, pp. 155-160.
[36] M. Caruso-Nicoletti, V. De Sanctis, M. Capra, G. Cardi- http://dx.doi.org/10.1002/ajh.22223
nale, L. Cucia, F. De Gregorio, A. Filosa, M. C. Gallati, [47] Y. Aydinok, S. Darcan, A. Polat, K. Kavakli, G. Nigli, M.
A. Lauriola, R. Malizia, A. Mangiagli, F. Massolo, C. Mas- Coker, M. Kantar and N. Cetingul, “Endocrine Complica-
trangelo, A. Meo, M. F. Messina, G. Ponzi, G. Raiola, L. tions in Patients with β Thalassemia Major,” Journal of
Ruggiero, G. Tamborino and A. Saviano, “Short Stature Tropical Paediatrics, Vol. 48, No. 1, 2002, pp. 50-54.
and Body Proportion in Thalassemia,” Journal of Pedia- http://dx.doi.org/10.1093/tropej/48.1.50
tric Endocrinology & Metabolism, Vol. 11, Suppl. 3, 1998, [48] M. Toumba, A. Sergis, C. Kanaris and N. Skordis, “Endo-
pp. 811-816. crine Complications in Patients with Thalassemia Major,”
[37] J. P. S. Chern, K. H. Lin, W. Y. Tsai, S. C. Wang, M. Y. Pediatric Endocrinology Reviews, Vol. 5, No. 2, 2007, pp.
Lu, D. T. Lin, K. S. Lin and S. H. Lo, “Hypogonadotropic 642-648.
Hypogonadism and Hematologic Phenotype in Patients [49] F. Najafipour, R. Sarisorkhabi, R. Bahrami, M. Zareizadeh,
with Transfusion Dependant Beta Thalassemia,” Journal K. Ghoddousi, N. Aghamohamazadeh, A. Aliasgharzadeh,
of Pediatric Haematology/Oncology, Vol. 25, No. 11, M. Mobaseri and M. Niafar, “Evaluation of Endocrine
2003, pp. 880-884. Disorders in Patients with Thalassemia Major,” Iranian
|http://dx.doi.org/10.1097/00043426-200311000-00011 Journal of Endocrinology and Metabolism, Vol. 10, No. 1,
[38] E. Y. Kwan, A. C. Lee, A. M. Li, S. C. Tam, C. F. Chan, 2008, pp. 35-43.
Y. L. Lau and L. C. Low, “A Cross Sectional Study of [50] M. F. Messina, F. Lombardo, A. Meo, M. Miceli, M. Was-
Growth, Puberty and Endocrine Function in Patients with niewska, M. Valenzise, C. Ruggeri, T. Arrigo and F. De
Thalassemia in Hong Kong,” Journal of Paediatrics and Luca, “Three-Year Prospective Evaluation of Glucose To-
Child Health, Vol. 31, No. 2, 1995, pp. 83-87. lerance, Beta-Cell Function and Peripheral Insulin Sensiti-
http://dx.doi.org/10.1111/j.1440-1754.1995.tb00752.x vity in Nondiabetic Patients with Thalassemia Major,”
[39] R. Chatterjee, T. N. Mukhopadhyay, S. Chandra and R. Journal of Endocrinological Investigation, Vol. 25, No. 6,

OPEN ACCESS OJEMD

32 P. DE ET AL.

2002, pp. 497-501. Cavallo and F. Di Gregorio, “Insulin Dependent Diabetes

[51] H. Cario, R. W. Holl, K. M. Debatin and E. Kohne, “In- in Thalassemia,” Archives of Disease in Childhood, Vol.
sulin Sensitivity and Beta-Cell Secretion in Thalassaemia 63, No. 1, 1988, pp. 58-62.
Major with Secondary Haemochromatosis: Assessment by http://dx.doi.org/10.1136/adc.63.1.58
Oral Glucose Tolerance Test,” European Journal of Pe- [63] H. Landau, I. Matoth, Z. Landau-Cordova, A. Goldfarb, E.
diatrics, Vol. 162, No. 3, 2003, pp. 139-146. A. Rachmilewitz and B. Glaser, “Cross Sectional and Longi-
[52] R. A. de Assis, A. A. Ribeiro, F. U. Kay, L. A. Rosemberg, tudinal Study of the Pituitary and Thyroid among Patients
C. H. Nomura, S. R. Loggetto, A. S. Araujo, A. F. Junior, M. with Thalassemia Major,” Clinical Endocrinology, Vol.
P. de Almeida Veríssimo, G. R. Baldanzi, B. P. Espósito, 38, No. 1, 1993, pp. 55-61.
R. H. Baroni, J. C. Wood and N. Hamerschlak, “Pancrea- http://dx.doi.org/10.1111/j.1365-2265.1993.tb00973.x
tic Iron Stores Assessed by Magnetic Resonance Imaging [64] S. Mariotti, F. Pigliaru, M. C. Cocco, A. Spiga, S. Vaquer
(MRI) in Beta Thalassemic Patients,” European Journal and M. E. Lai, “β-Thalassemia and Thyroid Failure: Is
of Radiology, Vol. 81, No. 7, 2012, pp. 1465-1470. There a Role for Thyroid Autoimmunity?” Pediatric En-
http://dx.doi.org/10.1016/j.ejrad.2011.03.077 docrinology Reviews, Vol. 8, Suppl. 2, 2011, pp. 307-309.
[53] R. Toccafondi, M. Maioli and T. Meloni, “Plasma Insulin [65] V. De Sanctis, C. Vullo, L. Urso, F. Rigolin, A. Cavallini,
Response to Oral Carbohydrate in Cooley’s Anemia,” Ri- K. Caramelli, C. Daugherty and N. Mazer, “Clinical Ex-
vista di Clinica Medica, Vol. 70, 1970, pp. 96-101. perience Using the Androderm Testosterone Transdermal
[54] N. McIntosh, “Endocrinopathy in Thalassemia Major,” System in Hypogonadal Adolescents and Young Men
Archives of Disease in Childhood, Vol. 51, No. 3, 1976, with Beta Thalassemia Major,” Journal of Pediatric En-
pp. 195-201. http://dx.doi.org/10.1136/adc.51.3.195 docrinology and Metabolism, Vol. 11, Suppl. 3, 1998, pp.
891-900.
[55] P. Cavallo-Perin, G. Pacini, F. Cerutti, A. Besone, C. Condo,
L. Scachetti, A. Piga and G. Pagano, “Insulin Resistance and [66] V. C. Canale, P. Steinherz, M. New and M. Erlandson,
Hyperinsulinemia in Homozygous β Thalassemia,” Meta- “Endocrine Function in Thalassemia Major,” Annals of
bolism, Vol. 44, No. 3, 1995, pp. 281-286. the New York Academy of Sciences, Vol. 232, 1974, pp.
http://dx.doi.org/10.1016/0026-0495(95)90155-8 333-345.
http://dx.doi.org/10.1111/j.1749-6632.1974.tb20597.x
[56] Z. Siklar, F. E. Citak, Z. Uysal, G. Öçal, M. Ertem, Ö.
Engiz, P. Adıyaman, T. İleri, S. Gözdaşoğlu and M. Ber- [67] F. Oberklaid and R. Seshadri, “Hypoparathyroidism and
beroğlu, “Evaluation of Glucose Homeostasis in Transfu- the Other Endocrine Dysfunction Complicating Thalas-
sion-Dependent Thalassemic Patients,” Pediatric Hema- semia Major,” Medical Journal of Australia, Vol. 1, No.
tology-Oncology, Vol. 25, No. 7, 2008, pp. 630-637. 10, 1975, pp. 304-306.
http://dx.doi.org/10.1080/08880010802313681 [68] M. D. Fliynn, A. Fairley, T. Jackson and B. E. Clayton,
[57] E. P. Vichinsky, “The Morbidity of Bone Disease in Tha- “Hormonal Changes in Thalassemia Major,” Archives of
lassaemia,” Annals of the New York Academy of Sciences, Disease in Childhood, Vol. 51, No. 11, 1976, pp. 828-836.
Vol. 850, 1998, pp. 344-348. http://dx.doi.org/10.1136/adc.51.11.828
http://dx.doi.org/10.1111/j.1749-6632.1998.tb10491.x [69] V. De Sanctis, R. Tanas, M. R. Gamberini, M. Sprocati,
[58] H. Cario, R. W. Holl, K. M. Debatin and E. Eohne, “Dis- M. R. Govoni and M. Marsella, “Exaggerated TSH Re-
proportionately Elevated Fasting Proinsulin Levels in Nor- sponse to TRH (‘Sub-Biochemical’ Hypothyroidism) in Pre-
moglycemic Patients with Thalassemia Major Are Correlated pubertal and Adolescent Thalassaemic Patients with Iron
to the Degree of Iron Overload,” Hormone Research in Pae- Overload: Prevalence and 20-Year Natural History,” Pe-
diatrics, Vol. 59, No. 2, 2003, pp. 73-78. diatric Endocrinology Reviews, Vol. 6, Suppl. 1, 2008, pp.
http://dx.doi.org/10.1159/000068572 170-173.
[59] K. Dmochowski, D. T. Finegood, W. Francombe, B. Tyler [70] V. Chirico, A. Lacquaniti, V. Salpietro, N. Luca, V. Ferraù,
and B. Zinman, “Factors Determining Glucose Tolerance B. Piraino, L. Rigoli, C. Salpietro and T. Arrigo, “Thyroid
in Patients with Thalassemia Major,” Journal of Clinical Dysfunction in Thalassemic Patients: Ferritin as Prognos-
Endocrinology and Metabolism, Vol. 77, No. 2, 1993, pp. tic Marker and Combined Iron Chelators as Ideal Therapy,”
478-483. European Journal of Endocrinology, 2013. [Epub ahead
of print]
[60] T. Arrigo, G. Crisaffilli, A. Meo, M. Sturiale, F. Lombardo,
M. Micelli, D. Cucinotta and F. De Cuca, “Glucose Tole- [71] A. Zervas, A. Katopodi, A. Protonotariou, S. Livadas, M.
rance in Insulin Secretion and Peripheral Sensitivity in Karagiorga, C. Politis and G. Tolis, “Assessment of Thy-
Thalassemia Major,” Journal of Pediatric Endocrinology roid Function in Two Hundred Patients with β-Thalassemia
& Metabolism, Vol. 11, Suppl. 3, 1998, pp. 863-866. Major,” Thyroid, Vol. 12, No. 2, 2002, pp. 151-154.
http://dx.doi.org/10.1089/105072502753522383
[61] M. Theochari, D. Loannidou, H. Nounopoulos, A. Bou-
loukos, M. Papadogiannis, M. Katsikari, T. Karpathios [72] A. Filosa, S. Di Maio, G. Aloj and C. Acampora, “Longi-
and C. S. Bartgocas, “Ultrasonography of the Pancreas as tudinal Study on Thyroid Function in Patients with Tha-
a Function Index in Children with Beta Thalassemia,” lassemia Major,” Journal of Pediatric Endocrinology and
Journal of Pediatric Endocrinology and Metabolism, Vol. Metabolism, Vol. 19, No. 12, 2006, pp. 1397-1404.
13, No. 3, 2000, pp. 303-306. http://dx.doi.org/10.1515/JPEM.2006.19.12.1397
http://dx.doi.org/10.1515/JPEM.2000.13.3.303 [73] S. Margo, P. Puzzanio, C. Consarino, M. C. Galati, S.
[62] V. De Sanctis, M. G. Zurlo, E. Senesi, C. Boffa, L. Morgione, D. Porcelli, S. Grimaldi, D. Tancre, V. Arcuri,

OPEN ACCESS OJEMD

 P. DE ET AL. 33

V. De Santis and A. Alberti, “Hypothyroidism in Patients brand, B. Bagni, T. Torressani, G. Tolis, M. Masiero, A.
with Thalassemia Syndromes,” Acta Haematologica, Vol. Di Palma and L. Borgatti, “Endocrine Abnormalities in Tha-
84, No. 2, 1990, pp. 72-76. lassemia,” Annals of the New York Academy of Sciences,
http://dx.doi.org/10.1159/000205032 Vol. 612, 1990, pp. 293-310.
[74] G. Depaz, A. Deville, N. Coussement, J. Manassero and R. http://dx.doi.org/10.1111/j.1749-6632.1990.tb24317.x
Mariani, “Thyroid Function in Thalassemia Major,” An- [86] V. De Sanctis and B. Wonke, “Growth and Endocrine
nales de Pediatrie (Paris), Vol. 32, 1985, pp. 809-811. Complications,” In: Growth and Endocrine Complications
[75] C. Phenekos, A. Karamerou, P. Pipis, M. Constantoulakis, in Thalassemia, Mediprint, Roma, 1998, pp. 17-30.
J. Lasaridis, S. Detsi and K. Politou, “Thyroid Function in [87] M. Goyal, P. Abrol and H. Lal, “Parathyroid and Calcium
Patients with Homozygous β Thalassemia,” Clinical En- Status in Patients with Thalassemia,” Indian Journal of
docrinology, Vol. 20, No. 4, 1984, pp. 445-450. Clinical Biochemistry, Vol. 25, No. 4, 2010, pp. 385-387.
http://dx.doi.org/10.1111/j.1365-2265.1984.tb03440.x http://dx.doi.org/10.1007/s12291-010-0071-5
[76] T. Alexandrides, N. Georgopoulos, S. Yarmenitis and A. [88] K. A. Autio, J. E. Mait, M. Lesser and P. J. Giardina, “Low
G. Vagenakis, “Increased Sensitivity to the Inhibitory Bone Mineral Density in Adolescents with β-Thalassemia,”
Function in Patients with Beta Thalassemia Major and Iron Annals of the New York Academy of Sciences, Vol. 1054,
Overload and the Subsequent Development of Hypothy- 2005, pp. 462-466.
roidism,” European Journal of Endocrinology, Vol. 143, http://dx.doi.org/10.1196/annals.1345.063
2000, pp. 319-325. [89] N. Bhamarapravati, S. Na-Nakorn, P. Wasi and S. Tuchin-
http://dx.doi.org/10.1530/eje.0.1430319 da, “Pathology of Beta Thalassemia Haemoglobin E Disease,”
[77] S. Mariotti, A. Loviselli, S. Murenu, F. Sau, L. Valentino, American Journal of Clinical Pathology, Vol. 47, 1967,
A. Mandas, S. Vacquer, E. Martino, A. Balestrieri and M. pp. 745-758.
E. Lai, “High Prevalence of Thyroid Dysfunction in Adult [90] M. Scacchi, L. Danesi, A. Cattaneo, E. Valassi, F. Pecori
Patients with Beta Thalassemia Major Submitted to Amio- Giraldi, P. Radaelli, A. Ambrogio, E. D’Angelo, N. Mirra,
darone Treatment,” Journal of Endocrinological Investiga- L. Zanaboni, M. D. Cappellini and F. Cavagnini, “The
tion, Vol. 22, No. 1, 1999, pp. 55-63. Pituitary-Adrenal Axis in Adult Thalassaemic Patients,”
[78] V. De Sanctis, M. Ughi, A. Pinamonti, M. Zachmann, T. European Journal of Endocrinology, Vol. 162, No. 1, 2010,
Torresani, R. Gamberini, A. Di Palma, B. Bagni, A. R. pp. 43-48. http://dx.doi.org/10.1530/EJE-09-0646
Cavallini and C. Vullo, “Growth Retardation in Thalas- [91] C. A. Sklar, L. Q. Lew, D. J. Yoon and R. David, “Adrenal
semia Major,” In: A. Prader and R. Rappaport, Eds., Cli- Function in Thalassemia Major Following Long-Term Treat-
nical Issues in Growth Disorders: Evaluation, Diagnosis ment with Multiple Transfusions and Chelation Therapy.
and Therapy, Freund publishing House Ltd., London, 1994, Evidence for Dissociation of Cortisol and Adrenal Andro-
pp. 31-47. gen Secretion,” American Journal of Diseases of Children,
[79] M. P. Senanayalee, S. A. Suraweera and H. D. Hubert, Vol. 141, No. 3, 1987, pp. 327-330.
“Thyroid Function in Thalassemia Major,” Ceylon Medi- http://dx.doi.org/10.1001/archpedi.1987.04460030105036
cal Journal, Vol. 44, No. 4, 1999, pp. 166-168. [92] P. Pasqualetti, D. Colantino, A. Collacciani, R. Casale and
[80] G. Zamboni, P. Marradi, F. Tagliaro, R. Dorizzi and L. Tatò, G. Natali, “Circadian Pattern of circulating Plasma ACTH,
“Parathyroid Hormone, Calcitonin and Vitamin D Metabo- Cortisol and Aldosterone in Patients with Beta Thalas-
lites in Beta-Thalassaemia Major,” European Journal of semia,” Acta Endocrinologica, Vol. 123, No. 2, 1990, pp.
Pediatrics, Vol. 145, No. 1-2, 1986, pp. 133-136. 174-178.
http://dx.doi.org/10.1007/BF00441875
[93] P. Poomthavorn, B. Isaradisaikul, A. Chuansumrit, P. Khlai-
[81] L. Even, T. Bader and Z. Hochbeg, “Diurnal Variation of rit, A. Sriphrapradang and P. Mahachoklertwattana, “High
Serum Calcium, Phosporus and PTH in the Diagnosis of Prevalence of ‘Biochemical’ Adrenal Insufficiency in Tha-
Hypoparathyroidism,” Pediatric Research (Abstract), 2001, lassemics: Is It a Matter of Different Testings or De-
pp. 3-141. creased Cortisol Binding Globulin?” Journal of Clinical
[82] N. G. Angelopoulos, A. Goula, G. Rombopoulos, V. Kalt- Endocrinology and Metabolism, Vol. 95, No. 10, 2010, pp.
zidou, E. Katounda, D. Kaltsas and G. Tolis, “Hypopa- 4609-4615. http://dx.doi.org/10.1210/jc.2010-0205
rathyroidism in Transfusion Dependant Patients with β [94] E. Drakonaki, O. Papakonstantinou, T. Maris, A. Vasilia-
Thalassemia,” Journal of Bone and Mineral Metabolism, dou, A. Papadakis and N. Gourtsoyiannis, “Adrenal Glands
Vol. 24, No. 2, 2006, pp. 138-145. in Beta-Thalassemia Major: Magnetic Resonance (MR)
http://dx.doi.org/10.1007/s00774-005-0660-1 Imaging Features and Correlation with Iron Stores,” Euro-
[83] A. Aleem, A. K. Al-Momem, M. Al-Harakati, A. Hassan pean Radiology, Vol. 15, No. 12, 2005, pp. 2462-2468.
and I. Al-Fawaz, “Hypocalcaemia Due to Hypoparathy- http://dx.doi.org/10.1007/s00330-005-2855-1
roidism in β Thalassemia Major Patients,” Annals of Saudi [95] V. De Sanctis, S. Stea, L. Savarino, D. Granchi, M. Visen-
Medicine, Vol. 20, No. 5-6, 2000, pp. 364-366. tin, M. Sprocati, R. Govoni and A. Pizzoferrato, “Osteo-
[84] F. Perignon, R. Brauner, J. C. Souberbielle, M. De Monta- chondrodystrophic Lesions in Chelated Thalassemic Patients:
lembert and R. Girot, “Growth and Endocrine Function in An Histological Analysis,” Calcified Tissue International,
Major Thalassemia,” Archives Françaises de Pédiatrie, Vol. 67, No. 2, 2000, pp. 134-140.
Vol. 50, No. 8, 1993, pp. 657-663. http://dx.doi.org/10.1007/s00223001121
[85] C. Vullo, V. De Sanctis, M. Katz, B. Wonke, A. V. Hoff- [96] C. E. Jensen, S. M. Tuck, J. E. Aquen, S. Koneru, R. W.

OPEN ACCESS OJEMD

34 P. DE ET AL.

Morris, A. Yardumian, E. Prescott, A. V. Hoffbrand and B. Density of Patients with Thalassemia Major: Four Year
Wonke, “High Prevalence of Low Bone Mass in Thalas- Follow Up,” Calcified Tissue International, Vol. 64, No.
semia Major,” British Journal of Haematology, Vol. 103, No. 6, 1999, pp. 481-484.
4, 1998, pp. 911-915. http://dx.doi.org/10.1007/s002239900637
http://dx.doi.org/10.1046/j.1365-2141.1998.01108.x [100] E. Voskaridou, M. C. Kyrtsonis, E. Terpos, M. Skordili, I.
[97] A. Filosa, A. Di Maios, A. Saviano, S. Vocca and G. Espo- Theodoropoulos, A. Bergele, E. Diamanti, A. Kalovidouris,
sito, “Can Adrenarche Influence the Degree of Osteopenia in A. Loutradi and D. Loukopoulos, “Bone Resorption Is In-
Thalassemic Children?” Journal of Pediatric Endocrino- creased in Young Adults with Thalassemia Major,” Bri-
logy and Metabolism, Vol. 9, No. 3, 1996, pp. 401-406. tish Journal of Haematology, Vol. 112, No. 1, 2001, pp.
http://dx.doi.org/10.1515/JPEM.1996.9.3.401 36-41.
[98] L. Ruggiero and V. De Sanctis, “Multicentre Study on Pre- http://dx.doi.org/10.1046/j.1365-2141.2001.02549.x
valence of Fractures in Transfusion Dependent Thalassemic [101] M. G. Vogiatzi, K. A. Autio, J. E. Mait, R. Schneider, M.
Patients,” Journal of Pediatric Endocrinology and Meta- Lesser and P. Giardina, “Low Bone Mineral Density in
bolism, Vol. 11, Suppl. 3, 1998, pp. 773-778. Adolescents with (Beta) Thalassemia,” Annals of the New
[99] E. Molyvda-Athanassopoulou, A. Sioundas, N. Karatzas, York Academy of Sciences, Vol. 1054, 2005, pp. 462-466.
M. Aggellaki, K. Pazaitou and I. Vainas, “Bone Mineral http://dx.doi.org/10.1196/annals.1345.063

OPEN ACCESS OJEMD