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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 3  |  Page : 770-777

Effect of abnormalities in leptin levels on pituitary–hypothalamic axis in patients with chronic hemolytic anemia


1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission31-Aug-2016
Date of Acceptance30-Oct-2016
Date of Web Publication15-Nov-2017

Correspondence Address:
Ahmed T Lasheen
Borg El-Kenanah, Shibin El-Kom, Menoufia, 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.218287

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  Abstract 

Objective
The aim this study was to investigate the serum leptin level and its pathological correlations in children with chronic hemolytic anemia.
Background
Thalassemia syndromes are hemoglobin disorders that result from significantly reduced or absent synthesis of either α-globin or β-globin chains. This results in chronic hemolytic anemia with high serum ferritin level, which affects serum leptin level through the influence of peripheral adipocytes.
Patients and methods
This is a comparative observational cross-sectional study carried out on 52 children diagnosed as having β-thalassemia major and 35 healthy children as controls. Patients with thalassemia were recruited from Pediatric Hematology–Oncology Unit of Menoufia University Hospital during the period from May 2015 to June 2015. All patients were assessed by full history taking, thorough clinical examination, and laboratory investigations including complete blood count; serum ferritin level; serum leptin level; thyroid function tests comprising thyroid stimulating hormone, T3, and T4; and blood sugar level.
Results
Weight, height, BMI, hemoglobin%, red blood cell counts, platelet count, and hematocrit were significantly lower in thalassemia group. Serum blood glucose level was significantly higher in thalassemia group. Serum ferritin level showed highly significant higher values in thalassemia group. Serum leptin, T3, T4, and thyroid stimulating hormone showed highly significant lower values in thalassemia group. There was a significant difference between male and female sex regarding serum leptin level. There were significant linear regression coefficients for correlations between leptin level and BMI, T4 level, and serum ferritin level.
Conclusion
Serum leptin level is significantly lower in patients with β-thalassemia major than healthy controls. This is associated with a significant inverse correlation between serum leptin level and serum ferritin level. There is a significant correlation between serum leptin and BMI and thyroxin hormone. Leptin deficiency proved to be a cofactor in the development of endocrinological complications in patients with thalassemia major.

Keywords: β-thalassemia major, chronic hemolytic anemia, pituitary–hypothalamic axis, serum leptin, thyroid dysfunction


How to cite this article:
El-Rasheidy FH, Essa ES, Mahmoud AA, Lasheen AT. Effect of abnormalities in leptin levels on pituitary–hypothalamic axis in patients with chronic hemolytic anemia. Menoufia Med J 2017;30:770-7

How to cite this URL:
El-Rasheidy FH, Essa ES, Mahmoud AA, Lasheen AT. Effect of abnormalities in leptin levels on pituitary–hypothalamic axis in patients with chronic hemolytic anemia. Menoufia Med J [serial online] 2017 [cited 2020 Jun 6];30:770-7. Available from: http://www.mmj.eg.net/text.asp?2017/30/3/770/218287


  Introduction Top


The thalassemia syndromes are hemoglobin disorders that result from significantly reduced or absent synthesis of either α-globin or β-globin chains. The result is a chronic hemolytic anemia with ineffective erythropoiesis and bone marrow overstimulation [1]. Frequent blood transfusion is a cornerstone in treatment of thalassemia, which in turn can result in iron overload and may lead to various complications, including various endocrine complications such as thyroid dysfunction [2]. Thyroid dysfunctions are well documented in patients with thalassemia major, requiring frequent and recurrent blood transfusions [3].

Leptin is a 146-amino acid polypeptide that is produced by adipocytes [4]. The receptor of this hormone, which is located in different parts of the body, not only regulates lipid and energy homeostasis but also affects neuroendocrine and immune function [5] Fat cells in children with β-thalassemia are not able to synthesize adequate amounts of leptin. Adipose tissue dysfunction is one of the reasons for hormonal abnormalities in patients with β-thalassemia major [6].

Leptin is mainly produced in the hypothalamus, and leptin deficiency causes premature consistent abnormalities in the pituitary–hypothalamic axis [7]. Its greatest influence is on the hypothalamus caused by JAK-STAT signal. This hormone probably affects the thyroid axis in hypothalamus by binding to its long receptor in the hypothalamus and activates JAK-STAT signal. Moreover, its influence on the paraventricular cores is effective for TRH gene regulation [8]. The aim of this study is to investigate the relationship between serum leptin level and thyroid dysfunction in children with chronic hemolytic anemia.


  Patients and Methods Top


This is a comparative observational cross-sectional study carried out on 52 children diagnosed as having β-thalassemia major and 35 healthy children as controls. Patients with thalassemia were recruited from the Pediatric Hematology–Oncology Unit of the Menoufia University Hospital during the period from May 2015 until June 2015. Their diagnosis was based on hematological parameters and hemoglobin electrophoresis. Healthy controls matched for socioeconomic, age, and sex were recruited from the Outpatient's Clinic of Pediatric Department, Menoufia University Hospital.

To be included in the study, patients should be diagnosed as having β-thalassemia major documented by clinical picture and hemoglobin electrophoresis. Patients should be receiving multiple blood transfusions at intervals of 2–4 weeks or had received at least 20 doses of regular packed red blood cell (RBC) transfusions. Patients should have high serum ferritin level, more than the normal level, which is 12–300 ng/ml for male patients and 12–150 ng/ml for female patients. All patients should be receiving single or combined iron chelation therapy. Age of the patients should be more than 10 years. Patients with any other hematological disorders and those with any sign of inflammation, infection, or diabetes mellitus were excluded from the study.

All patients were assessed by full history taking including personal history regarding name, age, sex, residence, and family pedigree. History of present illness was taken including presence of pallor, jaundice, or blood transfusion. Past history was taken including age of first blood transfusion, frequency of blood transfusion, age at the first chelation therapy, and presence or absence of cardiac lesion proved by echocardiography. Family history was taken including history of any member requiring frequent blood transfusion.

Thorough clinical examination was done for all patients including general examination for manifestations of the disease and any evidence of complications, anthropometric measurements (weight, height, and BMI), and abdominal examination.

Laboratory investigations for the study participants included complete blood picture using automated hemogram done for all cases including hemoglobin estimation, RBC counts, total leukocyte count, and platelet count. These parameters were obtained electronically by coulter counter model Beckman 750, Int, L.S.A (Beckman Coulter, Miami, U.S.A). Serum ferritin was detected in thalassemia and control groups by electrochemiluminescence. Serum leptin level was assessed using a sensitive enzyme-linked immunosorbent assay (ELISA) sandwich kit for both groups. Thyroid function tests including thyroid stimulating hormone (TSH), T3, and T4 were assessed for all study participants. Blood sugar level was assessed in the patient group.

Determination of leptin level in serum and plasma

Principle of the test

The DRG Leptin ELISA Kit is a solid-phase ELISA based on the sandwich principle. The microtiter wells were coated with a monoclonal antibody directed toward a unique antigenic site on a leptin molecule. An aliquot of specimen sample containing endogenous leptin was incubated in the coated well with a specific biotinylated monoclonal antileptin antibody. A sandwich complex was formed. After incubation, the unbound material was washed off and a streptavidin–peroxidase enzyme complex was added for detection of the bound leptin. Having added the substrate solution, the intensity of color developed is proportional to the concentration of leptin in the specimen sample.

Specimen collection

Serum or plasma can be used in this assay. Hemolytic, icteric, or lipemic specimen should be avoided. For serum collection, blood was collected by venipuncture and allowed to clot, and then the serum was separated by centrifugation at room temperature after complete clotting. For plasma collection, the entire blood was collected into centrifuge tubes containing anticoagulant and centrifuged immediately after collection.

Specimen dilution

In an initial assay, if a specimen is found to contain more than the highest standard, then the specimens can be diluted with standard 0 and reassayed as described in assay procedure. For the calculation of the concentrations, the following dilution factor had to be taken into account: dilution of 1: 10 = 10 μl serum + 90 μl standard 0 (mix thoroughly).

Assay procedure

All reagents and specimens were allowed to come to room temperature before use and mixed without foaming. Each run was including a standard curve. The desired number of microtiter wells was secured in the holder. We dispensed 15 μl of each standard, control, and sample with new disposable tips into appropriate wells. We dispensed 100 μl assay buffer into each well, and then thoroughly mixed for 10 s. The fluid is then incubated for 120 min at room temperature without covering the plate. This was followed by shaking out the contents of the wells briskly. The wells were rinsed three times with diluted wash solution (300 μl/well), and then the wells were struck sharply on absorbent paper to remove residual droplets. Then 100 μl of substrate solution was added to each well and incubated for 15 min at room temperature. The enzymatic reaction was stopped by adding 50 μl of stop solution to each well. Then the absorbance (optical density) of each well was determined at 450 ± 10 nm with a microtiter plate reader.

Calculation of results

At first, the average absorbance values for each set of standards, controls, and patient samples were calculated. Then a standard curve was constructed by plotting the mean absorbance obtained from each standard against its concentration, with absorbance value on the vertical (Y) axis and concentration on the horizontal (X) axis. Using the mean absorbance value for each sample, we could determine the corresponding concentration from the standard curve. Automated method: the results in the international field unit have been calculated automatically using a four parameter logistics curve fit. The four parameter logistics is the preferred method. Other data reduction functions may give slightly different results. The concentration of the samples can be read directly from this standard curve.

Statistical analysis

Results were collected, tabulated, and statistically analyzed with SPSS statistical package (version 20; SPSS Inc., Chicago, Illinois, USA). Overall, two types of statistics were calculated:

Descriptive statistics

Number and percentage were obtained for qualitative data and mean and SD for quantitative data.

Analytic statistics

Student's t-test is a test used for comparison between groups having quantitative variables. Mann–Whitney U-test (nonparametric test) is a test of significance used for comparison between two groups not normally distributed having quantitative variable. χ2-Test was used to study association between two qualitative variable. Receiver-operating characteristic curve was used to determine cutoff points; sensitivity and specificity for quantitative variables of interest; and 2 × 2 tables used for calculation of positive predictive value, negative predictive value, and diagnostic accuracy. Spearman's correlation coefficient test (r-test) is a test of significance used to study the correlation between nonparametric quantitative variables. Correlation coefficient test (r-test) results may be positive correlation or negative correlation. It is used to quantify the strength of the linear relationship between two variables. P value of less than 0.05 was considered statistically insignificant. P value less than or equal to 0.05 was considered statistically significant. P value less than or equal to 0.001 was considered statistically highly significant.


  Results Top


The current study included two groups: patient group (52 patients), consisting of 25 (48.1%) male and 27 (51.9%) female patients with mean ± SD age of 12.78 ± 2.36; and control group (35 patients), consisting of 14 (40%) male and 21 (60%) female individuals with mean ± SD age of 12.03 ± 0.82.

In the current study, there was a nonsignificant difference between the two groups regarding age and sex (P > 0.05). On the contrary, weight, height, and BMI were significantly lower in thalassemia group than in control group (P < 0.05 for all parameters) [Table 1].
Table 1: Demographic data and anthropometric measurements of the studied groups

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In the current study, the patients had a mean ± SD transfusion frequency of 3.46 ± 0.73 weeks. In total, 35 (67.3%) patients had a history of splenectomy, and 20 (38.5%) patients had a history of hydroxyurea intake. Regarding iron chelation therapy, 44 (84.6%) patients reported Desferal intake, 29 (55.8%) patients reported Exjade intake, and eight (15.4%) patients reported Ferriprox intake [Table 2].
Table 2: Clinical history among the studied group of patients (n=52)

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In the current study, hemoglobin%, RBC counts, platelet counts, and hematocrit value showed a highly significant decrease in thalassemia group than in control group (P < 0.001 for all). Serum blood glucose level was significantly higher in thalassemia group than in control group (P < 0.05 for all). There was a nonsignificant difference between the two groups regarding white blood cell count (P > 0.05) [Table 3].
Table 3: Complete blood count parameters and serum blood glucose among the studied groups

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In the current study, serum ferritin showed a highly significant higher values in thalassemia group compared with control group (P < 0.001). On the contrary, T3, T4, and TSH had highly significant lower values in thalassemia group compared with control group (P < 0.001 for all) [Table 4].
Table 4: Serum ferritin level and thyroid function tests among the studied groups

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In the current study, serum leptin level was lower in thalassemia group of patients than in control group of patients with a highly significant difference (P < 0.001) [Table 5].
Table 5: Serum leptin level among the studied groups

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The current study showed that in the group comprising patients with thalassemia, there was a nonsignificant correlation between age and serum leptin level (P = 0.51) and a significant difference between male and female sex regarding serum leptin level (P = 0.009). Moreover, group comprising patients with thalassemia showed a nonsignificant correlation between all growth parameters and serum leptin level except for BMI (P = 0.04) [Figure 1] and a nonsignificant correlation between serum leptin level and all laboratory investigations except for serum ferritin [Figure 2] and T4 levels (P = 0.009 and 0.03, respectively) [Table 6].
Figure 1: A line graph showing significant positive correlation between serum leptin level and BMI.

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Figure 2: A line graph showing significant negative correlation between serum leptin level and serum ferritin level.

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Table 6: Relationship between serum leptin level and demographic data, anthropometric measurements, and laboratory investigations among studied patients with thalassemia (n=52)

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In the current study, there were significant linear regression coefficients for correlations between leptin level and BMI, T4 level, and serum ferritin level (P < 0.05 for all) [Table 7].
Table 7: Unstandardized and standardized linear regression coefficients for correlations between leptin levels and BMI, T4 levels, and serum ferritin levels

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  Discussion Top


The current study investigated the possible difference in serum leptin level between patients with thalassemia and healthy controls and its possible correlation with serum ferritin level. It also investigated the relationship between serum leptin level and thyroid dysfunction in children with chronic hemolytic anemia. We chose patients with β-thalassemia major as representative for chronic hemolytic anemia because this type of hemolytic anemia is the commonest type presented to the outpatient clinic of pediatric hematology unit.

We focused on multitransfused children with β-thalassemia major because their high frequency of blood transfusion is expected to be associated with high serum ferritin level, which is known to be associated with increased incidence of hemosiderosis, which is a cause of multiple complications, including endocrinal complications, one of which is the effect on pituitary–hypothalamic axis [9],[10].

In the current study, there was a nonsignificant difference between case and control groups regarding age and sex (P > 0.05), indicating uniformity of the study groups. All growth parameters including weight, height, and BMI were significantly lower in patients with thalassemia group than in the control group (P < 0.05 for all). This matches the findings of Fahim et al. [11] who studied growth parameters in children with thalassemia major in upper Egypt and found that 49% of patients had short stature, 47% were underweight, and 3% had low BMI, each P value is less than 0.001.

In the current study, serum ferritin level were significantly high in the thalassemia group compared with control group (P < 0.001). This is in agreement with the result of Shahramian et al. [12] who found that the mean of serum ferritin level was significantly higher in the case group than in the control group (P < 0.05).

In the current study, the mean serum levels of T3, T4, and TSH were significantly lower in thalassemia group compared with control group (P < 0.001 for all). The mean serum levels of T3, T4, and TSH were 113.11 ± 14.81 ng/dl, 6.16 ± 1.1 μl/dl, and 1.79 ± 0.44 μIU/dl, respectively. Our findings are in agreement with Pirinççioǧlu et al. [13] who studied 90 children with β-thalassemia major and found that the means serum levels of T3, T4, and TSH were 160 ± 30 ng/dl, 9.0 ± 1.8 μg/dl, and 3.40 ± 3.8 μIU/ml, respectively, and these levels are within the reference intervals.

In the current study, serum leptin level was lower in patients with β-thalassemia than in control group with a highly significant difference (P < 0.001). Our results are in agreement with those reported by Choobineh et al. [6] who compared 219 patients with β-thalassemia major and 137 individuals without thalassemia and found that the serum leptin level median was significantly lower in patients with thalassemia (P < 0.001). Moreover, Moshtaghi-Kashanian and Razavi [14] assessed the blood levels of leptin in 97 patients with β-thalassemia, aged 12–18 years, and in 50 healthy individuals and found that serum leptin level was significantly lower in patients with β-thalassemia compared with healthy individuals. In addition, Chaliasos et al. [15] studied 28 patients with β-thalassemia and found that leptin was significantly lower in patients compared with controls (P = 0.0018).

However, these studies assessed patients with thalassemia in general with no specific predilection for pediatric age. However, Shahramian et al. [12] found that the mean serum level of leptin was significantly lower in thalassemia group than in control group (P < 0.05), and levels of leptin in case group showed a significant sex difference (P < 0.05).

In the current study, there was a nonsignificant correlation between age and serum leptin level in patients with thalassemia group (P = 0.51). This finding is different from that of Choobineh et al. [6] who found that leptin level and age were positively correlated among patients with β-thalassemia major (r = 0.234, P = 0.002). Also, Shahramian et al. [16] found a significant correlation between age and serum leptin level in 70 children with thalassemia major (r = 0.248, P = 0.041).

There was a significant difference between male and female sex in thalassemia group regarding serum leptin level (P = 0.009), being lower in the males. This result matches the finding of Choobineh et al. [6] who compared 119 male and 100 female patients with β-thalassemia major and found that males had significantly lower leptin level than females (P < 0.001). In addition, Shahramian et al. [16] found that the mean leptin levels in girls and boys with major thalassemia showed a significant difference (t = 2.74, P = 0.009).

In the current study, there was a nonsignificant correlation between weight and height and serum leptin level (P = 0.59 and 0.52, respectively). On the contrary, by linear regression analysis, there was a significant correlation between BMI and serum leptin level in patients with thalassemia group (P = 0.02). This can be attributed to the fact that the increased fat mass has led to an increase in leptin production [17].

This is in agreement with the results of Shahramian et al. [16] who found a significant correlation between BMI and leptin (r = 0.374, P = 0.002). On the contrary, Dayer et al. [18] found a significant correlation between BMI and leptin concentration in normal individuals (P = 0.009) but not in patients with thalassemia (P = 0.35). In addition, Choobineh et al. [6] found that leptin level and BMI had no significant correlation in patients with β-thalassemia major (P = 0.67). The difference between our study and these two studies can be attributed to unclear data about the thyroid status of the included patients in these two studies.

In the current study, by linear regression analysis, there was an inverse significant correlation between serum ferritin level and serum leptin level in patients with thalassemia group (P = 0.01). Our findings meet the results of Shahramian et al. [12] who found an inverse statistical correlation between the serum levels of leptin and ferritin among 90 children with β-thalassemia major (P < 0.05). In addition, Chaliasos et al. [15] found that leptin was negatively correlated with ferritin in 28 patients with β-thalassemia major (P = 0.032, r=−0.61).

The most probable reason for such relationship is the toxic effects of iron on cell membranes and proteins in patients with β-thalassemia major, as free iron causes peroxidative damage in lipid membrane and proteins with the generation of free oxygen radicals. Thus, in an iron overload (such as in β-thalassemia major) following the destructions of adipocyte, leptin level is decreased. Furthermore, the replacement of red BM with yellow BM which contains adipocytes (which is present in all individuals with hemolytic anemia according to the severity of the disease) can be the cause of this decrease [7].

In the current study, there was a nonsignificant correlation between serum leptin level and T3 and an inverse nonsignificant correlation between TSH and serum leptin level (P > 0.05 for both). On the contrary, and by linear regression analysis, there was a significant correlation between T4 and serum leptin level (P = 0.006). Leptin is mainly produced in the hypothalamus, and leptin deficiency causes premature consistent performance in the pituitary–hypothalamus axis. Its greatest influence is on the hypothalamus caused by JAK-STAT signal. This hormone probably affects the thyroid axis in hypothalamus by binding to its long receptor in the hypothalamus and activates JAK-STAT signal. Moreover, its effect on the paraventricular cores is effective for TRH gene regulation [7].

Our results are in agreement with Shahramian et al. [12] who found that there was a significant correlation between serum leptin levels and T4, but there was no significant correlation between serum leptin level and T3 and TSH. Also, Dayer et al. [18] found that there was no marked relationships between TSH and leptin concentrations in patients with thalassemia (r = −0.022, P = 0.909).


  Conclusion Top


Serum leptin level is significantly lower in patients with β-thalassemia major than healthy controls. This is associated with a significant inverse correlation between serum leptin level and serum ferritin level. This confirms the role of serum ferritin in lowering serum leptin level through its effect on peripheral adipocytes. There is a significant correlation between serum leptin and BMI and thyroxin hormone. Leptin deficiency proved to be a cofactor in the development of endocrinological disturbances through its effect on the hypophysis–hypothalamus axis in patients with thalassemia major.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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