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Changes in Kisspeptin, Growth and Thyroid Hormones in Thalassemic Patients of Pubertal Age Group.

Byline: Shazia Ali, Hizb Ullah and Sarwat Jahan

ABSTRACT

Beta thalassemia syndrome are a group of hereditary blood disorders in which or absent beta globin chain synthesis, results in reduced Hemoglobin, decreased RBC production and anemia. Total 300 individuals were divided into 4 groups according to age and gender i.e [?]13 years females, >13 years females, [?]13 years and >13 years males. Height in centimeter, weight in kilogram was measured to calculate BMI Kg/m2. Serum ferritin (ng/mL) and hemoglobin (gm/dl) alongwith hormonal assay of GH (ng/mL), T3 (ng/mL), T4 (ug/dL), TSH (uIU/mL), and kisspeptin (ng/ml) was done. BMI and hemoglobin were significantly reduced (P<0.001), while serum ferritin were significantly increased (P<0.001) in all four thalassemic groups on comparison with control. Kisspeptin levels were significantly reduced in [?]13 years female (P13 years of male (P<0.01).

T3 levels were significantly increased in both thalassemic groups of female (P<0.01). While T4 levels were significantly reduced in [?]13 years of male alongwith significantly reduced (P13 years male significantly increased (P<0.01) TSH levels were obtained. Growth hormone levels were significantly reduced (P<0.001) in both male and female thalassemic groups of [?]13 years. While significantly raised (P13 years. In >13 thalassemic female T3 had a negative correlation (P<0.05) with BMI and hemoglobin, while a positive correlation (P13 years male T3 had a positive correlation (P<0.05) with kisspeptin. T4 in all four thalassemic groups had a significant positive correlation with hemoglobin (P13 years female had a significant positive correlation with BMI, ferritin and hemoglobin (P1000 ng/ml lead to iron overload in various organ like heart, liver and endocrine gland (Olivieri and Brittenham, 1997; Vichinsky, 2001). Iron toxicity on the adipose tissue causes altered physiological function of leptin that affects body mass index (BMI) and body growth (D'anglemont et al., 2007; Plant and Durant, 1997). Definite levels of serum ferritin causing significant iron toxicity and organ damage are still unknown.

Advancement in medical treatment has improved the survival rate of thalassemic patients (Olivieri and Brittenham, 1997). Alongwith endocrine complications growth retardation is a frequent problem encountered by the thalassemic patients. Etiology of growth retardation is based on a number of factors like disease itself, toxic effects of the drugs used for chelation therapy (Caruso et al., 1998; De Sanctis et al., 1996), toxicity of iron overload and malnutrition and endocrine complications (Fuchs et al., 1997). The mechanism of growth retardation in these patients is not fully exemplified however, regarding endocrine complications along with thyroid and gonadal dysfunction (Roth et al., 1997; Jain et al., 1995), Growth Hormone (GH), insulin like growth factor (IGF),insulin like growth factor binding protein (IGFBP) also play an important role (Ashraf et al., 1998; Low et al., 1998).

Cause of retarded growth in thalassemic patient is complex and multi-factorial various factors like chronic hypoxia secondary to anemia (pre-transfusion Hb is below 8.5g/l), deficiency of Growth Hormone due to defective hepatic, biosynthesis of somatomedin, insulin like growth factor-1 (IGF-1) and sex steroid deficiency play main their role. Children treated with modern transfusion and chelation therapy are entering early adulthood so, evaluation of various endocrine complication secondary to iron overload can be evaluated in such individuals for future interventions. Therefore, exploration of the effects of iron overload on Kisspeptin and anterior pituitary hormones like GH, TSH and Thyroid hormones T3, T4 were evaluated. Also correlation of these hormones with body mass index (BMI), Ferritin and Hemoglobin (Hb) and Kisspeptin levels were further evaluated in beta thalassemic patients undergoing regular blood transfusion with chelation therapy.

MATERIALS AND METHODS

The present study included total 300 individuals out of which 200 were thalassemic patients and 100 were control matched for age and gender with the thalassemic group. The study was carried out after approval from Ethics committee of Quaid-e-Azam University. It was a case control study carried out at Quaid-e-Azam University in collaboration with Jamila Sultana Foundation, Thalassemia House, and Pakistan Institute of Medical Sciences (PIMS) from 2010-2014. The total individuals were divided into 4 groups according to age and gender i.e. [?]13 years females, >13 years females, [?]13 years and >13 years males. The patients selected for the study were diagnosed as beta thalassemia major according to hemoglobin electrophoresis. These patients were on regular blood transfusion with chelation therapy (desferroxamine injections). Informed consent and a detail proforma including history and clinical examination were filled on the patients visit to the thalassemia center.

Patients suffering from any other blood disorders other than beta thalassemia major or any other pathology besides spleen and liver enlargement or Hepatitis B and C were not included. Height in centimeter and weight in kilogram were measured to calculate the BMI Kg/m2. Serum ferritin (ng/mL) and hemoglobin (gm/dl) were done when patients came for their routine blood transfusions. The blood samples were taken for hormonal assay of GH (ng/mL), T3 (ng/mL), T4 (ug/dL), TSH (uIU/mL), and kisspeptin (ng/ml). The samples were collected in comfortable sitting position and arm rest was provided under the elbow. The sampling area was disinfected with a spirit swab. Blood sample (3ml) was drawn from the right median cubital vein of both female and male patients. Blood was then collected in labeled serum separator tubes containing Ethylene diamine tetra acetic acid (EDTA). The blood samples were centrifuged at 3000 rpm for 10 mins, and serum separated was stored at 2-8 0C until analyzed.

Serum hormone concentration for qualitative determination of GH was done by Enzyme Amplified Sensitivity Immunoassay, T3 was done by using Micro Particle Enzyme Immuno Assay (MEIA), while T4 was analyzed using Fluorescence Polarization Immunoassay (FPIA). TSH was detected by Chemiluminescent Microparticle Immunoassay (CMIA) and detection of specific peptide and its related peptides of kisspeptin were analyzed by using principal of competitive enzyme immuno assay (CEIA).

Statistical analysis

Data was analyzed through Graph Pad Prism 5.01, and data was reported as mean+-SEM. Comparison amongst hormones, BMI, hemoglobin and serum ferritin level with the control group was done by using unpaired t-test. Further non parametric co-relation (Spearman) was done for each hormone with rest of the variables through pad prism. P13 years had mean+-SEM of age 16.7+-0.42 years, whereas the female patients of >13 years had mean+-SEM of age 17.8+-0.70 years. Mean+-SEM of BMI, serum ferritin and hemoglobin levels of thalassemic and control groups are presented in Table I. BMI and hemoglobin levels in all thalassemic groups were significantly (P13years) significantly high (P<0.001) level of ferritin were noticed between the patient and corresponding control group. Comparison of serum kisspeptin levels in control and thalassemic male and female patients of different age groups are represented in Figure 1A.

Serum kisspeptin levels in thalassemic females [?]13 years (5.60+-0.26 ng/ml) were significantly lower (P13 years were 28.00+-0.76 ng/ml and were significantly higher (P<0.01) as compared to the control group (25.00+-0.18 ng/ml). Comparison of serum T3 levels of males and females thalassemic patients with their corresponding control of different age groups is shown in Figure 1B. Serum T3 levels in [?] 13 years thalassemic females (27.0+-8.44 ng/mL) was significantly higher (P13 years (1.88+-0.115 ng/mL) also had significantly higher (P13 years of age, there was no significant difference with the control groups.

Comparison of serum T4 levels of males and females thalassemic patients with their corresponding control of different age groups is shown in Figure 1C. Serum T4 levels in [?]13 years thalassemic male patients (6.60+-0.39 ug/dL) were significantly lower (P13 years males and [?]13 and >13 years thalassemic females were not significantly different from those in the control groups.

Serum TSH levels in thalassemic males and females of different age groups are shown in Figure 1D. Serum TSH levels in thalassemic females of [?] 13 years and >13 years females were not significantly different when compared with the control group, respectively. The serum TSH levels were significantly lower (P13 years thalassemic males (6.70+-1.2 uIU/mL) TSH levels were significantly higher (P<0.01) than the control group (1.40+-0.11 uIU/mL). Serum GH levels in thalassemic male and female patients of different age groups are shown in Figure 1E. Serum GH levels in thalassemic female [?]13 years were (1.33+-0.00 ng/ml) which were significantly low (P13 years (2.29+-0.30 ng/ml) had significantly high levels (P 13###Control (n=25)###23.1+-0.48###13.5+-0.26###150+-7.02

###Thalassemic (n=75)###13.7+-0.92***###6.71+-0.30***###3630+-368***

13###Males###Control (n=25)###21.8+-0.44###13.5+-0.28###75.8+-3.00

###Thalassemic (n=75)###17.2+-0.61***###7.06+-0.23***###4240+-255***

> 13###Control (n=25)###22+-0.45###15.00+-0.27###130+-13

###Thalassemic (n=75)###18+-0.63***###8.00+-0.47***###4300+-320***

Similarly, serum GH levels in thalassemic males of [?]13 years (0.55+-0.01 ng/ml) were significantly, lower than (P13 years (2.11+-0.31 ng/ml) were significantly raised as compared to the control group (0.36+-0.00 ng/ml) respectively. Correlation of T3 and T4 with BMI, serum ferritin, hemoglobin and kisspeptin levels in control and thalassemic males and females patients in different age groups is shown in Table II.

In thalassemic female of >13 years T3 has a significant (P<0.001) negative correlation with BMI (r= -0.408), (P<0.05) with Hb levels (r= -0.329). While T3 has a positive correlation (P<0.05) with serum ferritin levels of thalassemic males of [?] 13 years (r = 0.523) similarly, T3 has a positive correlation (P13 years.T4 has a significant positive correlation (P13 years of age. While T4 has a positive correlation (P<0.05) with Hb levels (r=0.332) in [?] 13 years thalassemic females. Similarly, T4 has a positive correlation (P 13 years of age and (P 13###Control (n=25)###0.443###0.441###0.311###0.155

###Thalassemia (n=75)###-0.408**###-0.038###-0.329*###0.243

13###Males###Control (n=25)###0.284###0.162###0.155###-0.122

###Thalassemic (n=75)###-0.263###0.523***###0.187###0.202

> 13###Control (n=25)###0.0734###0.018###0.107###0.460

###Thalassemic (n=75)###0.164###-0.207###0.208###0.317*

13###Females###T4###Control (n=25)###0.099###0.118###-0.237###0.083

###(ug/dL)###Thalassemia (n=75)###-0.196###0.137###0.332*###0.099

> 13###Control (n=25)###0.073###0.415###0.142###0.218

###Thalassemia (n=75)###0.333*###0.317*###0.328*###0.061

13###Males###Control (n=25)###-0.450###-0.351###-0.346###0.104

###Thalassemic (n=75)###-0.0173###-0.103###0.422**###-0.212

> 13###Control n=25###0.213###-0.191###-0.160###-0.101

###Thalassemic (n=75)###-0.229###-0.143###0.516***###0.064

13###Females###TSH###Control (n=25)###0.457###-0.138###0.083###-0.015

###(IU/mL)###Thalassemia (n=75)###-0.0627###-0.115###0.042###-0.052

> 13###Control (n=25)###0.215###0.151###0.059###0.194

###Thalassemia (n=75)###0.487***###0.531***###0.394**###0.021

13###Males###Control (n=25)###0.191###0.137###0.141###-0.118

###Thalassemic (n=75)###0.192###0.187###0.124###-0.056

> 13###Control (n=25)###0.174###0.599###0.524###-0.101

###Thalassemic (n=75)###0.064###0.446**###-0.197###-0.220

13###Females###Growth###Control (n=25)###-0.799###-0.099###-0.122###0.174

###Hormone###Thalassemic (n=75)###0.207###0.229###0.159###-0.009

###(ng/ml)

> 13###Control (n=25)###0.439###0.072###-0.146###-0.100

###Thalassemic (n=75)###0.016###-0.021###0.113###0.021

13###Males###Control (n=25)###-0.024###-0.348###-0.358###0.035

###Thalassemic (n=75)###0.091###0.043###0.005###0.310*

> 13###Control (n=25)###0.236###0.0###0.067###-0.761

###Thalassemic (n=75)###0.020###-0.012###-0.124###-0.101

In thalassemic females of > 13 years of age, TSH concentration showed highly significant (P<0.001) positive correlation between BMI (r= 0.487) and serum ferritin level (r= 0.531). Similarly, significant positive correlation (P<0.01) was observed with Hb levels (r=0.394); TSH had a positive correlation (P<0.01) with serum ferritin levels (r=0.446), and GH had a positive correlation with (P<0.05) with thalassemic males of [?]13 years (r=0.310).

DISCUSSION

Thalassemic patients are dependent on blood transfusions to maintain the levels of hemoglobin and packed cell volume in their blood. Transfusion and iron-chelation therapy has 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 (Abdulzahra et al., 2011). In our study, we observed that thalassemia major patients suffered from endocrine disorders and presented with delayed puberty. In another study carried out by Al-Rimawi et al. (2005) reported that there was a significant difference in the frequency and regularity of using chelation therapy between pubertal and delayed pubertal groups. Whereas in our study the age of starting chelation therapy was 6-8 months and the patients were on regular blood transfusion and chelation therapy.

In a previous study carried out by Al-Hakeim and Mohsen (2013), comparison of measured parameters between male and female thalassemic patients of 3-11 years of age group were done which showed high hemoglobin levels in male patients as compared to the female thalassemic patients. The change in hemoglobin levels can be easily explained by the genetic changes between male and female as males have higher hemoglobin levels than females (Al-Hakeim and Mohsen, 2013). While comparing with our study, hemoglobin levels of thalassemic males and females were significantly lower than that in the control groups. Similarly, we also observed that the serum ferritin level was higher than the control group which was similar to the results reported by Adil et al. (2012), suggesting that increased serum ferritin levels was related to the endocrinopathies involving various endocrine structures like pancreas, interior pituitary, thyroid, parathyroid and adrenal glands.

Increased serum ferritin levels were associated with increased incidence of endocrinopathies alongwith subsequent increase in the serum levels of calcium (Ca), alkaline phosphate and parathyroid hormone levels (Al-Hakeim and Mohsen, 2013). Thalassemic children frequently reflect growth retardation which may be attributed to their diversion from caloric resources resulting from ineffective erythropoiesis, alongwith the effects of anemia. Since hyper-transfusion has been shown to frequently restore normal growth rates, however, the adolescent growth spurt is often delayed, even in children who are hyper-transfused, unless intensive iron chelation therapy is instituted early in life (Viprakasit et al., 2001; Theodoridis et al., 1998).

Previous studies on thalassemic patients revealed that average age of 12+-8 years occasionally suffered from growth failure as 77.4% of these patients had normal BMI, while 4.8% were overweight and 6.5% were categorized as obese (Adil et al., 2012), whereas, thalassemic patients males and females of all groups included in the present study had reduced BMI (P13 years of thalassemic females were significantly higher than the control group. On comparison, serum T3 levels in thalassemic males [?] 13 and >13 years of age, there was no significant difference with the control groups.

Serum T4 levels in [?] 13 years thalassemic male patients were significantly lower (P<0.001) than the control group, whereas serum TSH levels were significantly lower (P13 years thalassemic males TSH levels were significantly higher (P13 years of age T3 had a significant (P<0.001) negative correlation with BMI (r= -0.408), (P<0.05) with Hb levels (r= -0.329), whereas T3 had a positive correlation (P<0.05) with serum ferritin levels of thalassemic males of [?] 13 years (r = 0.523). Similarly, T3 had a positive correlation (P13 years. T4 had a significant positive correlation (P13 years of age. T4 had a positive correlation (P<0.05) with Hb levels (r=0.332) in [?] 13 years thalassemic females.

Similarly, T4 showed a positive correlation (P 13 years of age and (P13 years of age. Moreover, GH had a positive correlation (P13 years of age. This is showing that hypothalamus production was correctly secreting kisspeptin and the levels of hormones secreted by anterior pituitary were also raised but there were reduced BMI and Hb levels in contrast to raised serum ferritin levels showing that hypothalamic pituitary axis was doing the proper production, whereas there might have been other factors involved in delaying the growth spurt. On the other hand, thalassemic females of >13 years also had raised levels of GH but low levels of kisspeptin and thyroid hormone, alongwith was reduced levels of BMI and Hb and raised serum ferritin levels.

These finding revealed that the response to chelation therapy could be one of the reasons why thalassemic females had reduced outcome, whereas thalassemic males and females of [?]13 years of age had reduced response of hypothalamic pituitary axis alongwith reduced BMI and Hb levels and raised serum ferritin levels. Among all, the three groups of [?]13 years thalassemic female and males and >13 years thalassemic females were effected by iron overload due to multiple transfusion.

ACKNOWLEDGEMENTS

The authors thank Jamila Sultana Foundation, Rawalpindi and Pakistan Institute of Medical Sciences (PIMS) for providing us thalassemic patients and allowing us to collect blood samples as well as carrying out general physical examination and history taking from the patients for this study. The authors would also like to thank Mr. Najam Khan for helping us formatting the article.

Statement of conflict of interests

The authors declare that they have no competing interests.

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Author:Ali, Shazia; Ullah, Hizb; Jahan, Sarwat
Publication:Pakistan Journal of Zoology
Article Type:Report
Geographic Code:9PAKI
Date:Jun 30, 2017
Words:4768
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