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4656
Journal of Applied Sciences Research, 9(8): 4656-4662, 2013
ISSN 1819-544X
This is a refereed journal and all articles are professionally screened and reviewed
ORIGINAL ARTICLES
Effect of Iron Overload on Function of Endocrine Glands in Egyptian Beta Thalassemia
Patients
1
Hegazi, M.A.M., 2Obada, M.A. and 3Elsheashaey, A.M.
1
Department of Zoology, Faculty of science, Tanta University, Tanta, Egypt.
Department of Clinical Biochemistry, National Liver Institute, Menoufia, Egypt.
3
Biological Researcher, Department of Clinical Biochemistry, National Liver Institute, Menoufia, Egypt.
2
ABSTRACT
Thalassemia is a hereditary disorder involving deficient synthesis of the hemoglobin polypeptide chains, its
treatment depends on regular blood transfusions and chelation therapy. Repeated transfusions and poor
compliance to therapy and chronicity of the disease lead to iron overload related complications including
endocrine complications (insufficiency of the pituitary, gonads and less commonly thyroid gland). Early
recognition of any defect in the activity of these glands is mandatory for the improvement of the quality of life
of these patients. This study was performed to evaluate of thyroid and gonadal functions in transfusiondependent beta-thalassemia patients. It was conducted on 54 patients with beta-thalassemia. In addition to 37
apparently healthy subjects matching age and gender served as a control group. According to age and gender
each of patients and controls were divided into 4 subgroups. Complete blood count and serum iron, ferritin,
thyroid function tests (TSH, FT3, and FT4), FSH, LH, estradiol, testosterone and progesterone hormones, were
measured for all participants in the study. The study revealed that there were a significant elevation of serum
iron and ferritin in patients compared to controls. The thyroid function tests showed no significant difference
between patients and controls. Meanwhile serum levels of gonadotropins and sex hormones were significantly
lower in patients as compared with controls. The results of this study reinforced the concept that iron overload in
transfusion-dependent patients with β-thalassemia deserves careful attention, and regular endocrine screening
during the first years of life in these patients is necessary for early detection and management of associated
complications.
Key words: thalassemia, ferritin, endocrine glands.
Introduction
Thalassemia is hemoglobin (Hb) disorder typed as quantitative disorder that passed down through families
in which the body makes an abnormal balance of hemoglobin, a disorder results in excessive destruction of red
blood cells (RBCs) and anemia(Cunningham, 2008).
Beta thalassemia may be the most well-known type of thalassemia. It causes variable anemia that can range
from moderate to severe, depending in part on the exact genetic change underlying the disease. Beta thalassemia
can be classified into thalassemia minor, intermedia and major (Galanello and Origa, 2010).
Treatment of thalassemia major includes regular blood transfusions and chelation therapy, the combination
of blood transfusion and chelation therapy has dramatically prolonged the life expectancy of these patients, thus
transforming thalassaemia from a rapidly fatal disease of childhood to a chronic disease compatible with a
prolonged life (Borgna-Pignatti et al., 2004; Khan, 2006).
However, frequent blood transfusions, iron overload, poor compliance to therapy and chronicity of the
disease have in turn contributed to a whole spectrum of complications including cardiac problems,
hypogonadism, hypothyroidism, hyperparathyroidism and other endocrine and metabolic problems (Satwani et
al., 2005).
Since several endocrine glands may be affected in patients with beta thalassemia major - and because their
life expectancy is now much longer - it is important that physicians be aware of the endocrine abnormalities that
may develop. One important aspect of management in polytransfused thalassemic patients is early recognition
and treatment of these endocrine dysfunctions (Abdulazahra et al., 2011; Pirinççioğlu et al., 2011).
The aim of this study was to evaluate thyroid and gonadal functions in transfusion-dependent betathalassemiapatients
Materials and Methods
The study was conducted on 91 subjects; 54 patients (groupI) with beta thalassemia, attending the out
patients clinic, Pediatric Department, National Liver Institute, Menoufia University in the period from February
Corresponding Author: Azza M. Elsheashaey, Biological Researcher, Department of Clinical Biochemistry, National Liver
Institute, Menoufia, Egypt.
E-mail: azza19722010@hotmail.
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J. Appl. Sci. Res., 9(8): 4656-4662, 2013
to June 2012. Their diagnosis was based on marked reduction of RBCS count and Hb concentration, CBC
picture (low MCV, MCH, and MCHC beside high reticulocytic count) and Hb electrophoresis (elevated levels
of HbA2 and HbF with low level or absent HbA). They were on regular blood transfusion, and received sub optimal iron chelating therapy started many months after the onset of blood transfusion. They have serum
ferritin values (>2000 ng/ml) which are much likely to be an indicator of iron overload state. In addition to 37
apparently healthy control subjects (groupII) matching age and gender of the patient group. Informed consent
was obtained from all participants in this work or from their parents, all members were subjected for: complete
history taking, clinical examination, laboratory investigations including: estimation of serum ferritin, thyroid
function tests; thyroid stimulating hormone, free thyroxin and free triiodothyronine (TSH, FT4, and FT3),
anterior pituitary hormones; luteinizing hormone and follicle stimulating hormone ( LH and FSH), gonadal
hormones; estradiol (E2), testosterone and progesterone using, chemiluminescent immunoassay based
IMMULITE 1000 ANALYZER. Siemens, USA, serum iron using the Architect automated immunoanalyzer
(Abbott Laboratories, Abbott Park, IL.) USA. And CBC using Sysmex KX-21, Japan.
Patients and controls were divided according to their ages into four subgroups:
-Group IA; included 19 thalassemic males with age ranged from 3. 4 to 12 years.
-Group IIA; included 10 control males with age ranged from 4 to12.4 years.
-Group IB; included 13 thalassemic males with age ranged from 14 to18 years.
-Group IIB; included 8 control males with age ranged from 13.8 to17.7 years.
-Group IC; included 10 thalassemic females with age ranged from 4 to 9.9 years.
-Group IIC; included 8 control females with age ranged from 3 to10 years.
-Group ID; included 12 thalassemic females with age ranged from 12 to18 years.
-Group IID; included 11 control females with age ranged from 12.5 to18 years.
Statistical analysis:
Data was statistically analyzed using SPSS (statistical package for social science) program. All data are
presented as mean ±standard deviation (SD),setting p < 0.05 for significance.
Results:
The mean age of thalassemic patients was 11.4±5.2 years, 32 (59.3%) were males, the mean age of controls
was 12.5±4.7 years, 18 (48.6%) were males. They were age and gender matched. Hb concentration and RBCs
counts decrease significantly in patient group compared to controls (p<0.05) while the mean serum levels of
iron and ferritin increase significantly in patients as compared with controls (p<0.05).The thyroid functions tests
(TSH, FT3 and FT4) showed no significant difference between patients and controls ( p>0.05) Table (1).
Table 1: Demographic features, mean laboratory tests, and thyroid function tests in the studied groups.
Studied variables
Group I
Group II
(n=54)
(n=37)
Mean ± SD
Mean ± SD
Age (years)
11.4 ±5.2
12.5 ±4.7
Test of
significance
p-value
U-test
1.05
>0.05
Gender (male/female)
32/22
18/19
X2
0.99
>0.05
Hb (g/dl)
7.29 ± 1.26
12.76 ± 1.34
t-test
19.89
t-test
10.32
<0.05
RBCs (million/ul)
3.25 ±
0.92
4.93 ± 0.45
<0.05
Iron (ug/dl)
182.13 ± 95.03
65.46 ± 30.48
U-test
6.83
<0.05
Ferritin (ng/ml)
4485.91 ± 2820.85
60.86 ± 43.95
<0.05
Free T3(pg/ml )
3.61 ± 0.88
3.6 ± 1.02
U-test
8.07
t-test
0.05
1.01 ± 0.12
3.18 ± 1.93
1.07 ± 0.16
3.39 ± 2.46
Free T4 (ng /dl )
TSH( μIU /ml )
t-test
2.12
U-test
0.09
>0.05
>0.05
>0.05
U-test= Mann Whitney test;P.value> 0.05 = non-significant; Hb= hemoglobin; RBCs= red blood cell count; Free T3= free triiodothyronine;
Free T4=free thyroxin and TSH= thyroid stimulating hormone
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J. Appl. Sci. Res., 9(8): 4656-4662, 2013
Regarding male groups, there was a significant elevation of the mean serum levels of iron and ferritin and a
significant decrease in the mean serum level of FSH (p value <0.05) in group IA compared to group IIA.
Meanwhile, no significant difference was detected between the two groups regarding LH (Table 2).
Table 2: Comparison between group IA and group IIA regarding some studies parameters.
Studied variables
Group IA
Group IIA
Test of significance
(n=19)
(n= 10)
Age (years)
7.43 ± 3.21
9.28 ± 2.19
U-test
1.45
Iron (μg/dl)
161.53± 72.65
50.8 ± 28.11
U-test
3.44
Ferritin (ng/ml)
3896.68±2203
73.9±50.77
U-test
4.36
LH( μIU /ml )
0.13 ± 0.1
0.38 ± 0.49
U-test
0.46
FSH( μIU /ml )
0.45 ± 0.24
1.55 ± 1.11
U-test
3.19
U-test= Mann Whitney test; LH=luteinizing hormone and FSH=follicle stimulating hormone
p-value
0.15
<0.05
<0.05
0.65
<0.05
Also, there was a significant elevation of the mean serum levels of iron and ferritin and a significant
decrease in the mean serum level of LH, FSH and testosterone (p value <0.05) in group IB compared to group
IIB Table (3).
Table 3: Comparison between group IB and group IIB regarding some studies parameters.
Studied variables
Group IB
(n=13)
Group IIB
(n=8)
Age (years)
15.66 ± 1.93
16.3 ± 1.41
Iron (μg/dl)
192.15 ± 40.52
58.5 ± 18.29
Ferritin (ng/ml)
5398.54± 3873.85
65.2 ± 48.88
LH( μIU /ml )
1.13 ± 1.28
5.39 ± 2.15
FSH( μIU /ml )
1.24 ± 1.04
5.61 ± 5.86
Testosterone (ng/dl)
66 ± 123.66
331.98 ± 173.76
Test of significance
p-value
t-test
0.81
t-test
8.73
U-test
3.77
U-test
5.72
U-test
2.66
U-test
4.11
0.43
<0.05
<0.05
<0.05
<0.05
<0.05
U-test= Mann Whitney test; LH=luteinizing hormone and FSH=follicle stimulating hormone
Regarding female groups, the mean serum level of LH showed asignificant decrease in group IC as
compared with group IIC, however the mean serum level of FSH showed no significant difference between the
two groups (table 4). Furthermore, there were significant decreases in the mean serum levels of LH, FSH,
progesterone and estradiol hormones (E2) in group ID compared to group IID (Table 5). The age of all patients
showed a significant positive correlation with ferritin, and a significant negative correlation with FT4. Also, a
significant negative correlation was noticed between ferritin and each of free T4 and FSH (data were not shown
in the tables).
Table 4: Comparison between group IC and group IIC regarding some studies parameters.
Studied variables
Group IC
Group IIC
Test of significance
(n=10)
(n=8)
Age (years)
7.0 ± 2.11
7.16 ± 2.82
U-test
0.40
Iron (μg/dl)
167.7 ± 88.42
77 ± 36.64
U-test
2.75
Ferritin (ng/ml)
3626.8 ± 1509.8
78.86 ± 43.85
U-test
3.55
LH( μIU /ml )
0.11 ± 0.09
0.15 ± 0.06
U-test
2.41
FSH( μIU /ml )
1.54±0.94
2.33 ± 2.09
U-test
0.62
U-test= Mann Whitney test; LH=luteinizing hormone and FSH=follicle stimulating hormone
p-value
0.69
<0.05
<0.05
<0.05
0.53
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J. Appl. Sci. Res., 9(8): 4656-4662, 2013
Table 5: Comparison between group ID and group IID regarding some studies parameters.
Studied variables
Group ID
Group IID
(n=12)
(n=11)
Age (years)
16.6 ± 2.65
16.52 ± 2.34
Test of significance
t-test
0.08
Iron (μg/dl)
215.92 ± 156. 2
75.45 ± 31.45
U-test
3.51
Ferritin (ng/ml)
5155.83 ± 3071.72
32.77 ± 17.45
U-test
4.06
LH( μIU /ml )
1.23±0.98
9.93±7.21
U-test
3.57
FSH( μIU /ml )
2.56±1.96
4.95±3.57
U-test
2.03
Progesterone (ng/ml)
2.21±4.41
4. 09±4.67
U-test
2.77
E2 (pg/ml)
22.91±17.41
108.17±107.45
U-test
2.86
U-test= Mann Whitney test; LH=luteinizing hormone; FSH=follicle stimulating hormone and E2 = estradiol
p-value
0.94
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
Discussion:
Thalassemia patients are dependent on blood transfusions to maintain the levels of hemoglobin and packed
cell volume in their blood.Transfusion and iron-chelation therapy have prolonged and improved the quality of
life in these patients (Borgna-Pignatti et al., 2004). Such a treatment, however, leads to chronic iron overload
affecting the endocrine glands(Abdulazahra et al., 2011).
In the current study a significant decrease was observed in Hb concentration and RBCs count and a
significant increase in the mean serum levels of iron and ferritin in patients as compared with control. These
findings are in agreement with Charles and Linker, (2005); Irshaid and Mansi, (2009)where they reported that
Hb concentration values in thalassemic patients are significantly lower than controls.
Similarly, Abdulzahra et al., (2011); Patil and Mujawar, (2010); Vahidi, et al., (2003) stated that iron
indices were markedly increased in thalassemia patients, and the mean serum level of ferritin was many times
higher than controls.
Thyroid dysfunction is known to occur frequently in thalassemia major, but its prevalence and severity
varies in different cohorts and the long-term natural history is poorly understood. Thyroid dysfunction is very
important, because hypothyroidism could be associated with growth problems so commonly seen in these
patients (Abdulzahra et al., 2011; Pirinççioğlu et al., 2011).
In the current study, thyroid function tests (free T4, free T3 and TSH) showed no significant difference
between thalassemic patients and controls.
These results agreed with findings reported from previous studies (Abdulzahra et al., 2011;Irshaid and
Mansi, 2009; Ong et al., 2008).
On the contrary, hypothyroidism was detected in different ratios in other studies done by Kurtoglu et al.,
(2012); De Sanctis et al., (2006) as they found hypothyroidism in 12.8%. 2.1% and 11% of their patients
respectively.
The diversity of these results could be explained by that the thyroid dysfunction in thalassemic patients is
depending on many factors such as the age of studied population, the duration of receiving blood transfusions,
the amount of iron overload, the dosage of iron-chelating agent, and the procedure used for evaluation
(Aruratanasirikul et al., 2007).
The present study detected a significant positive correlation between age and ferritin and a significant
negative correlation between ferritin and free T4.So, thyroid function tests might be affected with progress of
age of those patients and increased their serum ferritin level.
These findings are in line with Hashemizadeh and Norri, (2012); AL-Hader et al., (1993) where they found
that impaired thyroid function was associated with iron overload (expressed by ferritin). Also, Irshaid and
Mansi, (2009) reported that it is anticipated that the rate of thyroid dysfunctions increases steadily with
advancing age.
Controversially, Abdulzahra et al., (2011); Zervas et al., (2002) stated that no statistically significant
correlation was found between serum ferritin levels and thyroid functions.
Pituitary and gonadal dysfunctions; most frequently hypogonadism, which lead to growth retardation are
common problems in beta-thalassemia major patients. They are caused by iron overload (Al-Rimawi et al.,
2005;Papadimas et al., 1996). The current study detected a significant elevation of the mean serum levels of
each of iron and ferritin and a significant decrease in the mean serum level of FSH (p value <0.005) in group IA
compared to group IIA. Meanwhile, no significant difference was detected between the two groups regarding
LH.
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J. Appl. Sci. Res., 9(8): 4656-4662, 2013
Similarly, Dundar et al., (2007) found that the serum level of FSH in male thalassemia patients was
significantly lower compared to controls. Also, Masala et al., (1984) noticed that no significant difference was
found in the mean serum levels of LH.
In this work the mean serum levels of LH, FSH and testosterone were significantly lower in GIB compared
to GIIB.
In agreement with these results, Anoussakis et al., (2008); Dundar et al., (2007); Vahidi et al., (2003)
reported that patients with beta-thalassemia had lower serum LH, FSH and testosterone hormones levels than
the controls.
The mean serum levels of LH was significantly lower in GIC than GIIC (p<0.05). Meanwhile, the mean
serum level of FSH showed no significant difference between the two studied groups. Results which were in
accordance with the results of a study done by Dundar et al., (2007) on 25 patients with beta thalassemia major
as they found that the mean serum levels of LH was significantly lower in patients than controls.
In the current study, female thalassemia patients in GID had a significant decrease in the mean serum levels
of LH, FSH, progesterone, and E2 as compared with controls in GIID.
These findings matched results of a study done by Liavdas et al., (2008)as they found that the basal LH
values were lower in the thalassaemic patients than in the controls and did not increase significantly after
Luteinizing hormone releasing hormone (LHRH) administration. The FSH values were also lower in the
thalassaemic group compared to the controls, and increased only slightly after LHRH administration, and
explained these finding by presence of pituitary deficiency; mostly on gonadotrophs.
In a study done by Mula-Abed et al., (2008) hypogonadotropic hypogonadism was detected in 15 (50.0%)
of thalassemic patients (7 female and 8 male) with significant low levels of FSH and low LH with low E2 (in
females) or testosterone (in males).
The aforementioned results demonstrated that there was a significant alteration in the activity of
gonadotrophs in the anterior pituitary gland (LH and FSH), which takes place early in life and increases
affecting the function of the gonads at puberty, the main cause may be iron overload. Many previous
researches have shown a significant difference in serum ferritin levels between thalassemia patients with
endocrine complications and those without endocrinopathies (Abdulzahra et al., 2011). Also,Shamshirsaz et al.,
(2003) reported that there was a significant difference between mean serum ferritin in thalassemic patients with
endocrine complications and thalassemic patients without endocrinopathies.
These disorders have been proven to be the result of hemosiderosis of secretory cells such as the
gonadotroph cells of the pituitary gland (Abdelrazikand Ghanem, 2007;Shamshirsaz et al., 2003).
Many researchers have suggested that higher serum ferritin values (>2000 ng/ml) are likely to be an
indicator of iron overload state, as has been shown in different disorders (Abdelrazik, 2007;Ikram et al., 2004)
which is the case in the patients enrolled in this study (mean serum ferritin was 4485.9±2820.9 ng/ml).
However, in most clinical laboratories serum ferritin protein levels >400 ng/ml might define iron overload but,
in fact, such interpretation requires confirmation by the finding of a high percentage of saturation with iron of
the iron-binding capacity (transferrin) (Herbert el al., 1997).
The anterior pituitary is particularly sensitive to the iron overload (Skordis, 2011). And in thalassemia, iron
overload can affect both pituitary and gonadal function equally and simultaneouslyor either gland can be
affected predominantly and before the other (De Sanctis et al., 1988).
Other investigators demonstrated through (magnetic resonance imaging) pituitary gland atrophy in βthalassemic patients with hemochromatosis (Soliman et al., 2000) and the signal intensity reduction in the
anterior lobe of the pituitary gland correlated with serum ferritin level and the severity of pituitary dysfunction
(Sparacia et al., 2000). Furthermore, even a modest amount of iron deposition within the gland could interfere
with its function (De Sanctis, 2002).
Patients with transfusional iron overload began to develop pituitary iron overload in the first decade of life;
however, significant iron deposition were observed beginning in the second decade. Heavy pituitary iron
deposition were predictive of hypogonadotropic hypogonadism in these patients ( Noetzli et al., 2011) this
explains our results where the occurrence of pituitary and gonadal dysfunction is more in older age patients than
younger age patients. Also, in this study the serum levels of testosterone, progesterone and E2 were significantly
lower among thalassemic patients than controls (p< 0.05) indicating pituitary-gonadal dysfunction.
The present study found a significant negative correlation between serum ferritin levels and FSH in
accordance withPapadimas et al., (1996). These results confirmed the effect of iron overload on the activity of
the pituitary secretion of FSH.
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