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. Adipocytokines may play a role in the development of complications in β -thalassaemia

1. Correspondence: Yas¸ar Enli, MD, Department of Medical Biochemistry, Faculty of Medicine, Pamukkale University, Kinikli Kampusu, Morfoloji Binasi,
20070, Denizli, Turkey. Tel: ϩ90 532 7914727. Fax: ϩ90 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
YAS¸AR ENL 1,YASEM N I. BALCI2, CAFER GÖNEN1, EBRU UZUN2 & AZ Z POLAT2
Departments of 1Medical Biochemistry and 2Pediatric 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 significant.
Inflammatory 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 significantly higher in β-thalassemia minor patients than in controls. Adiponectin,
resistin and visfatin concentrations were significantly higher in both β-thalassemia intermedia and major patients than
in controls. The concentrations of adiponectin, resistin and visfatin were significantly higher in both β-thalassemia inter-
media and major patients than in β-thalassemia minor patients. There was no significant 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, inflamma-
tion is known to play an important role in the
development of complications of the disease. A chronic
inflammatory state is present in β-thalassemia patients,
with increased levels of inflammatory 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 inflammatory disorders [6].
Among these cytokines, much attention has been
paid to adiponectin, which has significant effects on
the inflammatory process [7]. Adiponectin attenu-
ates inflammation, 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 Healthcare
DOI: 10.3109/00365513.2014.883639
ScandJClinLabInvestDownloadedfrominformahealthcare.combyUniversityOfSouthAustraliaon08/11/14
Forpersonaluseonly.

2. Adipocytokines in b-thalassemia 307
Recent studies have shown the causative association
between resistin and systemic inflammation [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 proinflammatory
adipocytokine [13]. It can induce proinflammatory
cytokines such as IL-1, TNF, and IL-6 [14].
The role of adipocytokines in the inflammation
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 findings and hemoglobin elec-
trophoresis.The control group consisted of 30 healthy
children.
Patients with any other inflammatory, 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
Ϫ70°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 μg/L; linearity: 1.56–
100 μg/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 μg/L; linearity: 2.3–40 μg/L) by ELISA
kits (Phoenix, USA). These adipocytokines were
measured in duplicate. Serum concentrations of
adiponectin and visfatin were measured in μg/L,serum
resistin concentrations were measured in ng/L.
Statistical analysis
Since many variables had a non-Gaussian distribu-
tion with significant 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
coefficient. The data are expressed as median and
25–75 percentiles. Statistical significance was set at
pϽ0.05. 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 significantly higher in β-thalassemia
minor patients than in β-thalassemia intermedia and
β-thalassemia major patients (pϽ0.001). The RBC
distribution width (RDW) and ferritin concentra-
tions were significantly lower in β-thalassemia minor
patients than in β-thalassemia intermedia and β-
thalassemia major patients (pϽ0.001). The concen-
trations of ferritin (pϽ0.001) were significantly
lower in β-thalassemia intermedia patients than in
β-thalassemia major patients.
Ferritin was positively associated with adiponec-
tin (rϭ0.65, pϭ0.0001) and resistin (rϭ0.57,
pϭ0.0001) and visfatin (rϭ0.47, pϭ0.0001).
Serum levels of adipocytokines
Adiponectin, resistin, and visfatin serum concentra-
tions of all groups are shown in Table II.
Resistin (pϭ0.022) and visfatin (pϭ0.031) con-
centrations were significantly higher in β-thalassemia
ScandJClinLabInvestDownloadedfrominformahealthcare.combyUniversityOfSouthAustraliaon08/11/14
Forpersonaluseonly.

3. 308 Y. Enli et al.
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 17/12
BMI (kg/m2) 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 (1012/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 (μg/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; aControl vs. β-thalassemia minor (apϽ0.05, aapϽ0.01, aaapϽ0.001).
bControl vs. β-thalassemia intermedia (bpϽ0.05, bbpϽ0.01, bbbpϽ0.001). cControl vs. β-thalassemia major (cpϽ0.05, ccpϽ0.01,
cccpϽ0.001). dβ-thalassemia minor vs. β-thalassemia intermedia (dpϽ0.05, ddpϽ0.01, dddpϽ0.001). eβ-thalassemia minor vs. β-thalassemia
major (epϽ0.05, eepϽ0.01, eeepϽ0.001). fβ-thalassemia intermedia vs. β-thalassemia major (fpϽ0.05, ffpϽ0.01, fffpϽ0.001).
Table II. Serum concentrations of adipocytokines among different groups of β-thalassemia.
Control β-t* (minor) β-t (inter) β-t (major)
Adiponectin (μg/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 (μg/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; aControl vs. β-thalassemia minor (apϽ0.05, aapϽ0.01,
aaapϽ0.001). bControl vs. β-thalassemia intermedia (bpϽ0.05, bbpϽ0.01, bbbpϽ0.001). cControl vs. β-thalassemia major (cpϽ0.05,
ccpϽ0.01, cccpϽ0.001). dβ-thalassemia minor vs. β-thalassemia intermedia (dpϽ0.05, ddpϽ0.01, dddpϽ0.001). eβ-thalassemia minor vs.
β-thalassemia major (epϽ0.05, eepϽ0.01, eeepϽ0.001). fβ-thalassemia intermedia vs. β-thalassemia major (fpϽ0.05, ffpϽ0.01,
fffpϽ0.001).
minor patients than in controls. Adiponectin
(pϭ0.0001), resistin (pϭ0.0001) and visfatin
(pϭ0.0001) concentrations were significantly higher
in β-thalassemia intermedia patients than in controls.
Adiponectin (pϭ0.0001), resistin (pϭ0.0001)
and visfatin (pϭ0.0001) concentrations were sig-
nificantly lower in controls than β-thalassemia major
patients.
The concentrations of adiponectin (pϭ0.0001),
resistin (pϭ0.003) and visfatin (pϭ0.002) were
significantly higher in β-thalassemia intermedia
patients than in β-thalassemia minor patients.
Also, adiponectin (pϭ0.0001), resistin
(pϭ0.0001) and visfatin (pϭ0.005) concentrations
were significantly higher in β-thalassemia major
patients than in β-thalassemia minor patients.
There was no significant 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 inflammation. 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 inflammation. Endothelial cells
participate in atherogenesis and anti- and pro-
inflammatory 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, inflammation 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 elevatedTNF-α,
IL-1β 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 significantly increased in transfu-
sion-dependent TM patients and increased levels of
IL-6 indicate the presence of inflammatory 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
ScandJClinLabInvestDownloadedfrominformahealthcare.combyUniversityOfSouthAustraliaon08/11/14
Forpersonaluseonly.

4. 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 significant, was increasing.
Resistin is considered as a pro-inflammatory
cytokine [23]. Similar to adiponectin, resistin seems
to have immunomodulatory potential. Recombinant
human resistin increases the secretion of proinflam-
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 inflammatory 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 finding 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 proinflammatory effects of this
adipocytokine in human leukocytes [14]. Visfatin
might have direct proinflammatory 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 inflammatory 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 inflammation
such as type 2 diabetes, polycystic ovary syndrome
and inflammatory 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
inflammatory cytokines and may, in turn, up-regulate
the inflammatory 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 proinflammatory adipocytokines
(adiponectin, resistin, visfatin) with the severity of
beta-thalassemia types.
According to our findings, we speculate that these
proinflammatory adipocytokines play an important
role in the development of the complications of
β-thalassemias via inflammatory processes. From
this point, attenuation of proinflammatory 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 proinflammatory
adipocytokines and β-thalassemia types.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are respon-
sible for the content and writing of the paper.
References
Muncie HL Jr, Campbell J. Alpha and beta thalassemia. Am[1]
Fam Physician 2009;80:339–44.
Weatherall DJ. The thalassaemias. BMJ 1997;314:1675–8.[2]
Kanavaki I, Makrythanasis P, Lazaropoulou C, Tsironi M,[3]
Kattamis A, Rombos I, Papassotiriou I. Soluble endothelial
adhesion molecules and inflammation markers in patients
with beta-thalassemia intermedia. Blood Cells Mol Dis
2009;43:230–4.
KamadaY,Takehara T, Hayashi N. Adipocytokines and liver[4]
disease. J Gastroenterol 2008;43:811–22.
Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka[5]
M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T,
Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo
T, Kihara S, Yamashita S, Makishima M, Funahashi T,
Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I.
ScandJClinLabInvestDownloadedfrominformahealthcare.combyUniversityOfSouthAustraliaon08/11/14
Forpersonaluseonly.

5. 310 Y. Enli et al.
Visfatin: a protein secreted by visceral fat that mimics the
effects of insülin. Science 2005;307:426–30.
Anfossi G, Russo I, Doronzo G, Pomero A, Trovati M.[6]
Adipocytokines in atherothrombosis: focus on platelets and
vascular smooth muscle cells. Mediators Inflamm 2010;
2010:174341. doi: 10.1155/2010/174341.
Chaliasos N, Challa A, Hatzimichael E, Koutsouka F,[7]
Bourantas DK, Vlahos AP, Siamopoulou A, Bourantas KL,
Makis A. Serum adipocytokine and vascular inflammation
marker levels in Beta-thalassaemia major patients. Acta Hae-
matol 2010;124:191–6.
Chung CP, Long AG, Solus JF, Rho YH, Oeser A, Raggi P,[8]
Stein CM. Adipocytokines in systemic lupus erythematosus:
relationship to inflammation, insulin resistance and coro-
nary atherosclerosis. Lupus 2009;18:799–806.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee[9]
RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The
hormone resistin links obesity to diabetes. Nature 2001;
409:307–12.
Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ,[10]
Lazar MA. An inflammatory cascade leading to hyperre-
sistinemia in humans. PLoS Med 2004;2:161–8.
Bokarewa M, Nagaev I, Dahlberg L, Smith U,Tarkowski A.[11]
Resistin, an adipokine with potent proinflammatory proper-
ties. J Immunol 2005;174:5789–95.
Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD,[12]
Mickle DA. Resistin promotes endothelial cell activation:
further evidence of adipokineendothelial interaction. Circu-
lation 2003;108:736–40.
Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I.[13]
Cloning and characterization of the cDNA encoding a novel
human pre-B-cell colony-enhancing factor. Mol Cell Biol
1994;14:1431–7.
Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M,[14]
Niederegger H, Tilg H. Visfatin, an adipocytokine with
proinflammatory and ımmunomodulating properties. J
Immunol 2007;178:1748–58.
Hartge MM, Unger T, Kintscher U. The endothelium and[15]
vascular inflammation in diabetes. Diab Vasc Dis Res
2007;4:84–8.
Taher AT, Otrock ZK, Uthman I, Cappellini MD. Thalas-[16]
semia and hypercoagulability. Blood Rev 2008;22:283–92.
Aggeli C, Antoniades C, Cosma C, Chrysohoou C,Tousou-[17]
lis D, Ladis V, Karageorga M, Pitsavos C, Stefanadis C.
Endothelial dysfunction and inflammatory process in trans-
fusion-dependent patients with beta thalassemia major. Int
J Cardiol 2005;105:80–4.
Butthep P, Bunyaratvej A, FunaharaY, Kitaguchi H, Fucha-[18]
roen S, Sato S, Bhamarapravati N. Alterations in vascular
endothelial cell-related plasma proteins in thalassaemic
patients and their correlation with clinical symptoms.
Thromb Haemost 1995;74:1045–9.
Butthep P, Rummavas S, Wisedpanichkij R, Jindadamron-[19]
gwech S, Fucharoen S, Bunyaratvej A. Increased circulating
activated endothelial cells, vascular endothelial growth fac-
tor, and tumor necrosis factor in thalassemia. Am J Hematol
2002;70:100–6.
Kyriakou DS, Alexandrakis MG, Kyriakou ES, Liapi D,[20]
Kourelis TV, Passam F, Papadakis A. Activated peripheral
blood and endothelial cells in thalassemia patients. Ann
Hematol 2001;80:577–83.
Shitrit D, Tamary H, Koren A, Levin C, Bargil-Shitrit A,[21]
Sulkes J, Kramer MR. Correlation of vascular endothelial
growth factor with the severity of thalassemia intermedia.
Blood Coagul Fibrinolysis 2008;19:611–4.
Hovav T, Goldfarb A, Artmann G, Yedgar S, Barshtein G.[22]
Enhanced adherence of beta-thalassaemic erythrocytes to
endothelial cells. Br J Haematol 1999;106:178–81.
Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S,[23]
Ehtesham NZ. Human resistin stimulates the proinflamma-
tory cytokines TNF-alpha and IL-12 in macrophages by
NF-kappa betaB-dependent pathway. Biochem Biophys Res
Commun 2005;334:1092–101.
Yamamoto K, Kiyohara T, Murayama Y, Kihara S, Okamoto[24]
Y, FunahashiT, ItoT, Nezu R,Tsutsui S, Miyagawa JI,Tamura
S, Matsuzawa Y, Shimomura I, Shinomura Y. Production of
adiponectin, an anti-inflammatory protein, in mesenteric adi-
pose tissue in Crohn’s disease. Gut 2005;54:789–96.
Yu R, Xie S, Chen J, Zhang L, DaiY.The effects of PACAP[25]
and related peptides on leptin, soluble leptin receptor and
resistin in normal condition and LPS-induced inflamma-
tion. Peptides, 2009;30:1456–9.
Vozarova de Courten B, Degawa-Yamauchi M, Considine[26]
RV, Tataranni PA. High serum resistin is associated with an
increase in adiposity but not a worsening of insulin resis-
tance in Pima Indians. Diabetes 2004;53:1279–84.
McTernan PG, Fisher FM, Valsamakis G, Chetty R,[27]
Harte A, McTernan CL, Clark PM, Smith SA, Barnett AH,
Kumar S. Resistin and type 2 diabetes: regulation of resistin
expression by insulin and rosiglitazone and the effects of
recombinant resistin on lipid and glucose metabolism in
human differentiated adipocytes. J Clin Endocrinol Metab
2003;88:6098–106.
Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL,[28]
Murphy LJ. Plasma resistin, adiponectin and leptin levels in
lean and obese subjects: correlations with insulin resistance.
Eur J Endocrinol 2003;149:331–5.
Szapary PO, Bloedon LT, Samaha FF, Duffy D, Wolfe ML,[29]
Soffer D, Reilly MP, Chittams J, Rader DJ. Effects of pio-
glitazone on lipoproteins, inflammatory markers, and adi-
pokines in nondiabetic patients with metabolic syndrome.
Arterioscler Thromb Vasc Biol 2006;26:182–8.
Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT,[30]
Arafat H, Sarov-Blat L, O’Brien S, Keiper EA, Johnson AG,
Martin J, Goldstein BJ, Shi Y. Human epicardial adipose
tissue is a source of inflammatory mediators. Circulation
2003;108:2460–6.
Baker AR, Silva NF, Quinn DW, Harte AL, Pagano D,[31]
Bonser RS, Kumar S, McTernan PG. Human epicardial
adipose tissue expresses a pathogenic profile of adipocytok-
ines in patients with cardiovascular disease. Cardiovasc Dia-
betol 2006;5:1–7.
Ognjanovic S, Bao S, Yamamoto SY, Garibau-Tupas J,[32]
Samal B, Bryant-Greenwood GD. Genomic organization of
the gene coding for human pre-B-cell colony enhancing fac-
tor and expression in human fetal membranes. J Mol Endo-
crinol 2001;26:107–17.
Kralisch S, Klein J, Lossner U, Bluher M, Paschke R,[33]
Stumvoll M, Fasshauer M. Interleukin-6 is a negative regu-
lator of visfatin gene expression in 3T3-L1 adipocytes. Am
J Physiol Endocrinol Metab 2005;289:586–90.
Kralisch S, Klein J, Lossner U, Bluher M, Paschke R,[34]
Stumvoll M, Fasshauer M. Hormonal regulation of the novel
adipocytokine visfatin in 3T3-L1 adipocytes. J Endocrinol
2005;185:1–8.
Stephens JM,Vidal-Puig AJ.An update on visfatin/pre-B-cell[35]
colony enhancing factor, an ubiquitously expressed, illusive
cytokine that is regulated in obesity. Curr Opin Lipidol
2006;17:128–31.
Jia SH, Li Y, Parodo J, Kapus A, Fan L, Rotstein OD,[36]
Marshall JC. Pre-B cell colony-enhancing factor inhibits
neutrophil apoptosis in experimental inflammation and
clinical sepsis. J Clin Invest 2004;113:1318–27.
Ye SQ, Simon BA, Maloney JP, Zambelli-Weiner A,[37]
Gao L, Grant A, Easley RB, McVerry BJ, Tuder RM,
StandifordT, Brower RG, Barnes KC, Garcia JG. Pre-B-cell
colony-enhancing factor as a potential novel biomarker in
acute lung injury. Am J Respir Crit Care Med 2005;171:
361–70.
Sethi JK, Vidal-Puig A. Visfatin: the missing link between[38]
intra-abdominal obesity and diabetes? Trends Mol Med
2005;11:44–7.
ScandJClinLabInvestDownloadedfrominformahealthcare.combyUniversityOfSouthAustraliaon08/11/14
Forpersonaluseonly.

6. Adipocytokines in b-thalassemia 311
Haider DG, Holzer G, Schaller G, Weghuber D, Widhalm[39]
K,Wagner O Kapiotis S,Wolzt M. The adipokine visfatin is
markedly elevated in obese children. JPGN 2006;
43:548–9.
Tan BK, Chen J, Digby JE, Keay SD, Kennedy CR, Randeva[40]
HS. Increased visfatin messenger ribonucleic acid and pro-
tein levels in adipose tissue and adipocytes in women with
polycystic ovary syndrome: parallel increase in plasma visfa-
tin. J Clin Endocrinol Metab 2006;91:5022–8.
Chen MP, Chung FM, Chang DM, Tsai JC, Huang HF,[41]
Shin SJ, Lee YJ. Elevated plasma level of visfatin/pre-B cell
colony-enhancing factor in patients with type 2 diabetes
mellitus. J Clin Endocrinol Metab 2006;91:295–9.
Lopez-Bermejo A, Chico-Julia B, Fernandez-Balsells M,[42]
Recasens Esteve E, Casamitjana R, Ricart W, Fernández-
Real JM. Serum visfatin increases with progressive beta-cell
deterioration. Diabetes 2006;55:2871–5.
Berndt J, Kloting N, Kralisch S, Kovacs P, Fasshauer M,[43]
Schon MR, Stumvoll M, Blüher M. Plasma visfatin concen-
trations and fat depot-specific mRNA expression in humans.
Diabetes 2005;54:2911–6.
Pagano C, Pilon C, Olivieri M, Mason P, Fabris R, Serra R,[44]
Milan G, Rossato M, Federspil G,Vettor R. Reduced plasma
visfatin/pre-B cell colony-enhancing factor in obesity is not
related to insulin resistance in humans. J Clin Endocrinol
Metab 2006;91:3165–70.
Yang H, Lavu S, Sinclair DA. Nampt/PBEF/Visfatin: a reg-[45]
ulator of mammalian health and longevity? Experim Geron-
tol 2006;41:718–26.
Bae SK, Kim SR, Kim JG, Kim JY, Koo TH, Jang HO,[46]
Yun I,Yoo MA, Bae MK. Hypoxic induction of human vis-
fatin gene is directly mediated by hypoxia-inducible factor-1.
FEBS Lett 2006;580:4105–13.
Segawa K, Fukuhara A, Hosogai N, Morita K, Okuno Y,[47]
Tanaka M, NakagawaY, Kihara S, Funahashi T, Komuro R,
Matsuda M, Shimomura I.Visfatin in adipocytes is upregu-
lated by hypoxia through HIF1alpha-dependent mechanism.
Biochem Biophys Res Commun 2006;349:875–82.
Kendal CE, Bryant-Greenwood GD. Pre-B-cell colonyen-[48]
hancing factor (PBEF/Visfatin) gene expression is modu-
lated by NF-kappaB and AP-1 in human amniotic epithelial
cells. Placenta 2006;28:305–14.
ScandJClinLabInvestDownloadedfrominformahealthcare.combyUniversityOfSouthAustraliaon08/11/14
Forpersonaluseonly.