Correspondence: Ya s ar Enli, MD, Department of Medical Biochemistry, Faculty of Medicine, Pamukkale University, Kinikli Kampusu, Morfoloji Binasi, 20070, Denizli, Turkey. Tel: � 90 532 7914727. Fax: � 90 258 2961765. E-mail: enli21@yahoo.com

(Received 12 August 2013 ; accepted 12 January 2014 )

ORIGINAL ARTICLE

Adipocytokine concentrations in children with different types of beta-thalassemia

YA S AR ENL 1 , YASEM N I. BALCI 2 , CAFER G Ö NEN 1 , EBRU UZUN 2 & AZ Z POLAT 2

Departments of 1 Medical Biochemistry and 2 Pediatric Haematology , Pamukkale University , Faculty of Medicine , Denizli , Turkey

Abstract Background . Beta-thalassemia is an inherited blood disorder. It results from the impaired production of β -globin chains, leading to a relative excess of alpha-globin chains. Clinical severity separates this disease into three main subtypes: β -thalassemia major, β -thalassemia intermedia and β -thalassemia minor, the former two being clinically more signifi cant. Infl ammatory processes may play an important role in some of the complications of thalassemia. Adipose tissue is one of the most important endocrine and secretory organs that release adipocytokines like adiponectin, resistin and visfatin. Aim . The aim of our study was to analyze adipocytokine concentrations (adiponectin, resistin and visfatin) in different types of β -thalassemia patients and determine any possible correlations with disease severity. Methods . We recruited 29 patients who were transfusion-dependent β -thalassemia-major patients, 17 patients with β -thalassemia intermedia, 30 β -thalassemia minor patients. The control group consisted of 30 healthy children. Anthropometric measurements, complete blood count, biochemical parameters, serum concentrations of adiponectin, resistin, visfatin were performed for all subjects. Results . Resistin and visfatin concentrations were signifi cantly higher in β -thalassemia minor patients than in controls. Adiponectin, resistin and visfatin concentrations were signifi cantly higher in both β -thalassemia intermedia and major patients than in controls. The concentrations of adiponectin, resistin and visfatin were signifi cantly higher in both β -thalassemia inter-media and major patients than in β -thalassemia minor patients. There was no signifi cant difference between β -thalassemia intermedia and β -thalassemia major patients for adipocytokines concentrations. Conclusion . We speculate that these adipocytokines may play a role in the development of complications in β -thalassaemia.

Key Words: Beta-thalassemia , adipocytokine , adiponectin , resistin , visfatin

Introduction

Beta-thalassemias are a group of of hereditary blood disorders characterized by impaired production of the beta-globin chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals [1]. Three main forms have been described: Thalassemia Major, variably referred to as ‘ Cooley ’ s Anemia ’ and ‘ Mediterranean Anemia ’ , Thalassemia Intermedia and Thalassemia Minor also called ‘ β -thalassemia carrier ’ , ‘ β -thalassemia trait ’ or ‘ heterozygous β -thalassemia ’ [2].

Although β -thalassemia is a hereditary haemoglo-binopathy caused by defective haemoglobin β -globin synthesis, leading to excess alpha-globin chains that cause haemolysis and impair erythropoiesis, infl amma-tion is known to play an important role in the

development of complications of the disease. A chronic infl ammatory state is present in β -thalassemia patients, with increased levels of infl ammatory cytokines [3].

Some of these adipocytokines are adiponectin, resistin, visfatin, leptin, plasminogen activator inhib-itor type 1 (PAI-1), tumor necrosis factor α (TNF- α ), IL-6 and IL-8 [4,5].

Adipocytokines are considered important players in the etiopathogenesis of numerous metabolic, vascular and infl ammatory disorders [6].

Among these cytokines, much attention has been paid to adiponectin, which has signifi cant effects on the infl ammatory process [7]. Adiponectin attenu-ates infl ammation, oxidative stress, and cytokine production.

Resistin is a member of the resistin-like molecule family of cysteine-rich secretory 12-kDa proteins [8].

Scandinavian Journal of Clinical & Laboratory Investigation, 2014; 74: 306–311

ISSN 0036-5513 print/ISSN 1502-7686 online © 2014 Informa HealthcareDOI: 10.3109/00365513.2014.883639

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Adipocytokines in b -thalassemia 307

Recent studies have shown the causative association between resistin and systemic infl ammation [9,10], especially in the vascular endothelium [11].

Visfatin (PBEF), a recently discovered 52-kDa adipocytokine, is preferentially produced in and secreted from visceral adipose tissue, which is strongly associated with the metabolic syndrome [12]. Visfatin can be considered a new proinfl ammatory adipocytokine [13]. It can induce proinfl ammatory cytokines such as IL-1, TNF, and IL-6 [14].

The role of adipocytokines in the infl ammation process in β -thalassemia has been investigated in literature. But, there is no study about these adipo-cytokines in different types of β -thalassemia.

The aim of our study was to analyze adipocytok-ines, which are adiponectin, resistin and visfatin, concentrations in different types of Turkish β -thalassemia patients and determine any possible correlations with disease severity.

Materials and methods

A total of 76 patients and 30 healthy subjects were included in our study. We recruited 29 patients who were transfusion-dependent β -thalassemia patients (thalassemia major), 17 patients with β -thalassemia intermedia and 30 β -thalassemia minor patients. The diagnosis of β -thalassemias had been made by CBC (complete blood count), peripheral blood smear, physical examination fi ndings and hemoglobin elec-trophoresis. The control group consisted of 30 healthy children.

Patients with any other infl ammatory, infectious, chronic or hereditary diseases were excluded. Also, patients on medications other than iron chelators and splenectomized patients were excluded in our study. All of the β -thalassemia major patients were using the iron chelator (deferasirox, 10 – 30 mg/kg/day).

The study was approved by the Pamukkale Uni-versity Ethics Committee. Informed consent form was taken from the parents.

Body mass indexes (BMI) were calculated by dividing the weight in kilograms by the square of the height in metres. Full history and thorough clinical examination, anthropometric measurements, com-plete blood count, biochemical parameters, serum concentrations of adiponectin, resistin, visfatin using enzyme linked immuno sorbant assay (ELISA) were performed for all subjects.

Blood samples were collected from β -thalassemia major patients just before a scheduled transfusion and after an overnight fast of 10 – 12 h. From all other patients and healthy children, blood samples were obtained after an overnight fast of 10 – 12 h.

Serum obtained from blood was separated after centrifugation for 15 min at 3,000 rpm at 4 ° C, separated into aliquots and immediately stored at � 70 ° C until assayed.

Red blood cell indices (complete blood count) were measured using a routine automated method (Siemens ADVIA ® 2120i System, Siemens Health-care Diagnostics, Japan). Serum ferritin concentra-tions were measured with Roche Cobas 6000 autoanalyser (Roche-Hitachi Diagnostics, Japan) by using electrochemiluminescence method.

Enzyme immunoassay for adipocytokines were assayed by enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer ’ s recommended procedure. Serum concentrations of adiponectin (sensitivity: 0.06 μ g/L; linearity: 1.56 – 100 μ g/L) and resistin (sensitivity: 3 ng/L; linearity: 78 – 5000 ng/L) were determined by ELISA kits (Boster Immunoleader, China) and visfatin (sensitiv-ity: 1.85 μ g/L; linearity: 2.3 – 40 μ g/L) by ELISA kits (Phoenix, USA). These adipocytokines were measured in duplicate. Serum concentrations of adiponectin and visfatin were measured in μ g/L, serum resistin concentrations were measured in ng/L.

Statistical analysis

Since many variables had a non-Gaussian distribu-tion with signifi cant skewness, statistical analysis was performed with non-parametric tests: Kruskal-Walis and Mann-Whitney U. Correlations between vari-ables were calculated with Spearman ’ s correlation coeffi cient. The data are expressed as median and 25 – 75 percentiles. Statistical signifi cance was set at p � 0.05. Data were analyzed with the SPSS (Statis-tical Package for the Social Science, version 17.0).

Results

Table I shows the demographic and laboratory char-acteristics of groups. The concentrations of haemo-globin (Hb), hematocrit (Hct), red blood cell count (RBC) were signifi cantly higher in β -thalassemia minor patients than in β -thalassemia intermedia and β -thalassemia major patients ( p � 0.001). The RBC distribution width (RDW) and ferritin concentra-tions were signifi cantly lower in β -thalassemia minor patients than in β -thalassemia intermedia and β -thalassemia major patients ( p � 0.001). The concen-trations of ferritin ( p � 0.001) were signifi cantly lower in β -thalassemia intermedia patients than in β -thalassemia major patients.

Ferritin was positively associated with adiponec-tin ( r � 0.65, p � 0.0001) and resistin ( r � 0.57, p � 0.0001) and visfatin ( r � 0.47, p � 0.0001).

Serum levels of adipocytokines

Adiponectin, resistin, and visfatin serum concentra-tions of all groups are shown in Table II.

Resistin ( p � 0.022) and visfatin ( p � 0.031) con-centrations were signifi cantly higher in β -thalassemia

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Table I. Demographic and laboratory characteristics of groups.

Control β -t * (minor) β -t (inter) β -t (major)

Age (years) 8.5 (6.0 – 11.3) 9.0 (7.0 – 14.0) 9.0 (4.5 – 15.0) 11.0 (7.0 – 15.0)Male/Female 18/12 17/13 10/7 17/12BMI (kg/m 2 ) 16.6 (15.0 – 17.4) ccc 16.8 (14.7 – 18.8) 15.6 (14.8 – 17.0) ff 18.3 (16.5 – 19.9)Hb (g/dl) 13.3 (12.7 – 13.8) aaa, bbb, ccc 11.0 (10.5 – 11.5) ddd, eee 7.5 (6.8 – 8.9) ff 8.8 (8.2 – 9.3)Hct (%) 38.3 (37.0 – 40.0) aaa, bbb, ccc 33.3 (32.0 – 36.4) ddd, eee 26.0 (21.5 – 26.9) 26.0 (24.3 – 27.7)RBC (10 12 /L) 5.25 (5.00 – 5.93) bbb, ccc 5.50 (5.18 – 5.70) ddd, eee 3.70 (3.40 – 3.94) ff 3.20 (3.00 – 3.40) MCV (fL) 78.3 (76.0 – 80.9) aaa, bbb, ccc 63.1 (60.0 – 65.3) eee 64.0 (55.5 – 66.0) 59.0 (54.9 – 61.7) RDW (%) 15.0 (14.6 – 16.0) aaa, bbb, ccc 18.0 (17.0 – 18.8) ddd, eee 24.0 (23.5 – 26.3) f 21.9 (16.7 – 24.6) Ferritin ( μ g/L) 35 (20 – 53) a, bbb, ccc 45 (30 – 65) ddd, eee 739 (573 – 1084) fff 1585 (1029 – 2116)

All the values are shown as median and 25 – 75 percentiles. * β -thalassemia; Hb, haemoglobin; Hct, hematocrit; RBC, red blood cell count; MCV, mean corpuscular volume; RDW, RBC distribution width; a Control vs. β -thalassemia minor ( a p � 0.05, aa p � 0.01, aaa p � 0.001). b Control vs. β -thalassemia intermedia ( b p � 0.05, bb p � 0.01, bbb p � 0.001). c Control vs. β -thalassemia major ( c p � 0.05, cc p � 0.01, ccc p � 0.001). d β -thalassemia minor vs. β -thalassemia intermedia ( d p � 0.05, dd p � 0.01, ddd p � 0.001). e β -thalassemia minor vs. β -thalassemia major ( e p � 0.05, ee p � 0.01, eee p � 0.001). f β -thalassemia intermedia vs. β -thalassemia major ( f p � 0.05, ff p � 0.01, fff p � 0.001).

Table II. Serum concentrations of adipocytokines among different groups of β -thalassemia.

Control β -t * (minor) β -t (inter) β -t (major)

Adiponectin ( μ g/L) 1494 (1388 – 1788) bbb, ccc 1524 (1229 – 2136) ddd, eee 2598 (1947 – 3179) 3259 (2200 – 3736) Resistin (ng/L) 2272 (1719 – 2611) a, bbb, ccc 2502 (2198 – 2955) ddd, eee 3324 (2816 – 4250) 3586 (3014 – 4276)Visfatin ( μ g/L) 11.0 (10.6 – 11.3) a, bbb, ccc 11.3 (10.8 – 11.8) ddd, ee 12.2 (11.4 – 13.9) 12.0 (11.1 – 14.7)

All the values are shown as median and 25 – 75 percentiles. * β -thalassemia; a Control vs. β -thalassemia minor ( a p � 0.05, aa p � 0.01, aaa p � 0.001). b Control vs. β -thalassemia intermedia ( b p � 0.05, bb p � 0.01, bbb p � 0.001). c Control vs. β -thalassemia major ( c p � 0.05, cc p � 0.01, ccc p � 0.001). d β -thalassemia minor vs. β -thalassemia intermedia ( d p � 0.05, dd p � 0.01, ddd p � 0.001). e β -thalassemia minor vs. β -thalassemia major ( e p � 0.05, ee p � 0.01, eee p � 0.001). f β -thalassemia intermedia vs. β -thalassemia major ( f p � 0.05, ff p � 0.01, fff p � 0.001).

minor patients than in controls. Adiponectin ( p � 0.0001), resistin ( p � 0.0001) and visfatin ( p � 0.0001) concentrations were signifi cantly higher in β -thalassemia intermedia patients than in controls.

Adiponectin ( p � 0.0001), resistin ( p � 0.0001) and visfatin ( p � 0.0001) concentrations were sig-nifi cantly lower in controls than β -thalassemia major patients.

The concentrations of adiponectin ( p � 0.0001), resistin ( p � 0.003) and visfatin ( p � 0.002) were signifi cantly higher in β -thalassemia intermedia patients than in β -thalassemia minor patients.

Also, adiponectin ( p � 0.0001), resistin ( p � 0.0001) and visfatin ( p � 0.005) concentrations were signifi cantly higher in β -thalassemia major patients than in β -thalassemia minor patients.

There was no signifi cant difference between β -thalassemia intermedia and β -thalassemia major patients for adipocytokines concentrations.

Discussion

In β -thalassemia, the defect in the individual β -globin gene alone cannot fully explain the diversity of various complications such as cardiovascular prob-lems or chronic vascular infl ammation. Chronic hae-molysis, increased adhesiveness of erythrocytes and platelets to endothelial cells, oxidative stress and chronic iron overload participate in the endothelial damage and vascular infl ammation. Endothelial cells

participate in atherogenesis and anti- and pro-infl ammatory responses due to their ability to pro-duce and detect cytokines and their expression of adhesion molecules under certain circumstances [15]. Due to the wide range of functions in which the endothelial cells participate, endothelial dysfunc-tion, injury and activation may participate in numer-ous disease processes including atherosclerosis, diabetes, pulmonary hypertension, infl ammation and the hemoglobinopathies, including β -thalassemias.

In β -thalassemia patients, where vascular com-plications are frequent, there is strong evidence of endothelial cell activation and impaired endothe-lial function [15 – 17]. Endothelial activation in β -thalassemia patients is indicated by increased concentrations of circulating activated endothelial cells in these individuals, as well as elevated TNF- α , IL-1 β and vascular endothelial growth (VEGF) [18,19]. Furthermore, concentrations of vascular endothelial growth factor have been shown to cor-relate with the severity of TI [20]. Concentrations of sVCAM-1, sICAM-1 and sE-selection are reported to be signifi cantly increased in transfu-sion-dependent TM patients and increased levels of IL-6 indicate the presence of infl ammatory processes in individuals [17,19], possibly the result of oxidative stress due, once again, to iron overload. In addition to endothelial cell activation, erythrocytes and leuko-cytes from β -thalassemia individuals have been shown to display enhanced adherence to endothelial cells

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Adipocytokines in b -thalassemia 309

and sub-endothelial protein, possibly contributing to endothelial activation [21,22].

In thalassemia, the activated and damaged endothelial cells could be the direct source of the increased adiponectin. Adiponectin may take part in the equilibrium between the release of cytokines and adhesion molecules from the endothelium. Elevated adiponectin may be the expression of a counter-regulatory response aimed at mitigating the endothe-lial damage and cardiovascular risk in these patients [7].

In our study, we found the similar results for adiponectin concentrations in different types of β -thalassemia patients. Adiponectin concentrations were increasing while the severity of disease, β -thalassemia major and β -thalassemia intermedia being clinically more signifi cant, was increasing.

Resistin is considered as a pro-infl ammatory cytokine [23]. Similar to adiponectin, resistin seems to have immunomodulatory potential. Recombinant human resistin increases the secretion of proinfl am-matory cytokines such as TNF-alpha, IL-6, and IL-12 in murine and human macrophages [10,24]. In addition, human endothelial cells are activated by recombinant human resistin [10], leading to increased expression of endothelin 1 and several adhesion mol-ecules as well as chemokines in these cells. Resistin may contribute to the development of obesity [25], insulin resistance [26,27] and the metabolic syn-drome [28]. Plasma resistin concentrations increase with increasing infl ammatory mediator levels, pre-dicting the severity of coronary atherosclerosis [29].

Similarly, we found that resistin concentrations were lower in controls than other groups. At the same time, the concentrations of resistin in β -thalassemia major and β -thalassemia intermedia patients were higher than in the other two groups (control and β -thalassemia minor). This fi nding indicates that similar results with adiponectin and resistin concen-tration changes according to the disease severity.

PBEF/Nampt/visfatin has been recently charac-terized as a novel adipocytokine [5]. It was demon-strated potent proinfl ammatory effects of this adipocytokine in human leukocytes [14]. Visfatin might have direct proinfl ammatory responses in cor-onary artery disease pathogenesis [30,31]. Previous studies have shown that visfatin expression is regu-lated by cytokines that promote insulin resistance, such as lipopolysaccharide, interleukin (IL)-1, tumour necrosis factor (TNF) and IL-6 [32 – 34]. A compelling body of evidence suggests a role for vis-fatin as a mediator of the infl ammatory response. The pathophysiological role of visfatin/PBEF in humans is controversial and remains largely unknown [35]. It is upregulated in obesity and in states of insulin resistance, but also exerts insulin mimetic effects in various tissues [36 – 38]. Circulating visfatin has been found to be increased in obesity and in other disor-ders related to insulin resistance and infl ammation

such as type 2 diabetes, polycystic ovary syndrome and infl ammatory bowel disease; progressive β -cell deterioration is also paralleled by increasing visfatin concentrations [39 – 42]. In contrast, other studies have found no relationship between circulating vis-fatin, insulin sensitivity or visceral fat mass and have reported no differences in visfatin gene expression between subcutaneous and visceral adipose tissue [43,44]. Visfatin has been described as a longevity protein that delays replicative senescence and enhances resistance to oxidative stress [36,45]. Visfatin is up-regulated by infection, hypoxia and infl ammatory cytokines and may, in turn, up-regulate the infl ammatory cascade [46 – 48].

Our study demonstrated that the serum concen-trations of visfatin were higher in β -thalassemia major and β -thalassemia intermedia patients compared to β -thalassemia minor patients and controls. Like pre-vious two cytokine levels, visfatin concentrations were increasing as the β -thalassemia diseases severity were increasing.

In conclusion, all results of the our study demon-strate that a novel association between the increasing concentrations of proinfl ammatory adipocytokines (adiponectin, resistin, visfatin) with the severity of beta-thalassemia types.

According to our fi ndings, we speculate that these proinfl ammatory adipocytokines play an important role in the development of the complications of β -thalassemias via infl ammatory processes. From this point, attenuation of proinfl ammatory adipocy-tokines or augmentation of the function of adiponec-tin, resistin and visfatin might be an effective therapy for the prevention of the complications of β -thalassemias.

Further clinical and experimental research should elucidate the relationship between proinfl ammatory adipocytokines and β -thalassemia types.

Declaration of interest : The authors report no confl icts of interest. The authors alone are respon-sible for the content and writing of the paper.

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