EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
Abdul-Fattah et al
ANEMIA OF CHRONIC DISEASE IN RHEUMATOID ARTHRITIS
PATIENTS: POSSIBLE ROLE OF HEPCIDIN AND TNF-α
By
Abdul-Fattah ME*, Ghobrial GA**, El-Labban A*** and Abdul-Naser A***
Departments of *Internal Medicine, **Clinical -Pathology
and ***Rheumatology & Rehabilitation
Minia Faculty of Medicine
ABSRTRACT:
Background: Rheumatoid arthritis (RA) is a chronic disease of undetermined cause
that is associated with significant disability. Anemia of chronic disease (ACD) is a
well recognized extra-articular feature. Hepcidin is a recently discovered hormone
that appears to be a key regulator of systemic iron homeostasis. However, the role of
this hormone in ACD in RA patients had not been investigated. Cytokines play an
important role in rheumatoid arthritis, of these cytokines tumor necrosis factor-α
(TNF-α) seems to play a role in pathogenesis of anemia of chronic disease (ACD) in
patients with RA.
Aim of the study: To evaluate the role of hepcidin and TNF-α in anemia of chronic
disease associated with rheumatoid arthritis.
Subjects and methods: We evaluated serum prohepcidin (as an indicative to
hepcidin level) and TNF-α in a group of 30 patients with rheumatoid arthritis
suffering from ACD, in addition to 10 healthy subjects as a control group.
Results: In patients with rheumatoid arthritis, a significant increase in serum prohepcidin and TNF-α levels had been observed (292.23±103.89 ng/ml and 78.56±
35.87 pg/ml) when compared to control group (223.60±76.80 ng/ml and 26.40±16.06
pg/ml) (p = 0.038 and p=0.001 respectively).
Also, both serum prohepcidin levels and TNF-α correlated negatively with
hemoglobin level (p=0.019 and p=0.003 respectively). A trend towards positive
correlation had been observed between serum prohepcidin and TNF-α (p= 0.06).
Conclusion: This study provides evidence that both hepcidin and TNF-α are involved
in the development of ACD in patients with rheumatoid arthritis.
KEY WORDS:
Anemia of chronic disease
TNF-α
Hepcidin
Rheumatoid arthritis
INTRODUCTION:
Rheumatoid arthritis (RA) is a
prevalent
systemic
inflammatory
disease that mainly affects the joints.
This disease affects about 1% of the
human population. Although the
etiology and pathogenesis of this
disease are not yet fully understood it
seems that an autoimmune-mechanism
plays a crucial role in RA (Swaak,
2006).
The most frequent extraarticular manifestation in RA is anemia,
and although rarely acknowledged as
such, it can affect 60% of all patients
with RA at least once during their
lifelong disease course (Wolfe and
Michaud, 2006).
Anemia not only contributes to
fatigue and reduced quality of life in
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EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
RA, but longstanding anemia can have
deleterious cardiovascular effects and
contribute to increased mortality
(Swaak, 2006).
Abdul-Fattah et al
be a contributing factor in the
pathogenesis of anemia of chronic
disease (Fleming, 2008).
However the exact role of this
hormone is the pathogenesis of ACD in
RA patients is not yet clear.
Anemia in RA patients can be
accounted for by iron deficiency and/or
less often by reduced vitamin B-12 or
folic acid levels. However, the most
common form of anemia in this
patients group is anemia of chronic
disease (ACD). Although many
theories have been proposed to explain
possible mechanisms underlying ACD
in RA patients, its pathogenesis is still
unclear (Nissenson et al., 2003).
ACD is not just a matter of
disturbed iron metabolism; in addition
it is associated with impaired erythropoietin production, impaired response
of the erythroid marrow to erythropoietin and a diminished pool of
erythropoietin responsive cells (Nicolas
et al., 2002).
Substantial evidence indicates
that inflammatory cytokines subserve a
crucial role in joint destruction and
disease propagation in RA patients.
Among these cytokines, tumor necrosis
factor α (TNF-α), which has been
considered as the pivotal factor in
inducing and sustaining tissue damage.
Apart from its detection in the inflamed
synovial fluid, TNF-α is also found in
elevated levels in patient sera.
Moreover it had been postulated to
correlate with disease activity.
Furthermore, circumstantial evidence
suggests that increased local TNF-α
production in the bone marrow may be
implicated in the pathogenesis of
anemia of chronic disease in RA
patients (Papadaki et al., 2002).
One of the main underlying
mechanisms of anemia of chronic
disease (also termed as anemia of
inflammation) is the disturbance of
iron homeostasis, with increased
uptake and retention of iron within
cells of the reticuloendothelial system.
This leads to a diversion of iron from
the circulation into storage sites of the
reticuloendothelial system, subsequent
limitation of the availability of iron for
erythroid progenitor cells and ironrestricted erythropoiesis (Nikolaisen et
al., 2008).
Hepcidin
is
a
recently
discovered
mediator
of
innate
immunity, which had been suggested
to be a key regulator of iron
homeostasis (Park et al., 2001).
Hepcidin, previously reported as liverexpressed antimicrobial-peptide, is a
circulating
hormone
mainly
synthesized in the liver by hepatocytes.
Studies had reported that hepcidin
regulates intestinal iron absorption and
affects the release of iron from hepatic
stores and from macrophages involved
in the recycling of iron from
hemoglobin. Furthermore, hepcidin is
an acute phase peptide and its production is increased in inflammation. It
has been proposed that hepcidin may
In view of these findings, we
investigated levels of serum prohepcidin, the pro-hormone form of
hepcidin and TNF-α in a cohort of
patients with RA with ACD to identify
if either or both play role in the
pathogenesis of ACD in RA patients.
SUBJECTS AND METHODS:
A. Subjects:
This study was conducted at ElMinia University Hospital, and
included 30 RA patients with ACD. In
addition 10 healthy subjects, who were
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age and sex matched to the patients
group, were included as a control
group.
Abdul-Fattah et al
Routine laboratory tests:
Chemistry (ALT, AST, bilirubin,
urea and creatinine) were done by fully
automated machine (Dimension ES,
USA). CRP was done by turbidmetric
assay, Kits was supplied by Spinreact,
Spain. ESR was done by Westergrenn
method. CBC was performed on
automated hematology analyzer (Sysmex-K 800, Japan). Serum iron was
done by colorimetric method (Biocon,
Germany). Serum ferritin was done by
ELISA (TECO Diagnostics USA).
All patients satisfied 4 or more
of the revised American College of
Rheumatology (ACR) criteria for
classifycation of Rheumatoid arthritis
(Arnett et al., 1988).
Anemia was defined in
accordance with the World Health
Organization (WHO) criteria, as
presence of hemoglobin levels < 13.0
g/dl for men and < 12.0 g/dl for
women, in a manner similar to Wolfe
and Michaud (2006).
Pro-hepcidin serum assessment:
Determination of serum prohepcidin concentration in serum was
carried out by commercially available
solid phase enzyme-linked immunosorbent assay (ELISA) kits, obtained
from DRG (Heidelberg, Germany, Ref:
RE 54051). The detection limit was 4.0
ng/ml.
ACD was defined as anemia in
associated with serum ferritin level >
50 ng/ml. (Intragumtornchai et al.,
1998 and Vreugdenhil et al., 1990).
Exclusion criteria included: 1)
Patients with iron deficiency anemia,
as diagnosed by a low mean
corpuscular volume (< 80 fl) with
serum ferritin level < 50 ng/ml 2)
Presence of any other acute or chronic
medical illness 3) bedridden or post
operative state 4) blood transfusion
within the last 3 months 5) patients
who received erythropoietin and/or
iron treatment or who had recent
history of bleeding were also excluded.
Serum TNF-:
TNF- was quantified in serum
using ELISA method (Endogen, USA).
The sensitivity of which is 4.0 pg/ml.
The absorbance of each well was read
at 450 nm and a standard curve was
constructed to quantitate the TNF- 
concentration in the assay samples.
Statistical Analysis:
Statistical
analyses
were
performed using SPSS statistical
package. Values are presented as mean
±SD, unless otherwise mentioned.
Comparison between groups was by
unpaired t-test for normally distributed
date and Mann-Whitney U-test for data
that were not normally distributed.
Evaluation of the correlation was
performed using Pearson and Spearman single correlation coefficient
analysis. For categorical data CHI
square test was used. Multiple linear
logistic regression was done for
Methods:
Blood Sampling and Laboratory
Procedures
Blood samples were collected
from all participants in 3 tubes (Plain,
citrated for ESR and K3 EDTA for
CBC). After centrifugation, serum was
collected and stored at -70oC till
further analysis of serum prohepcidin
and TNF-α.
The following laboratory tests were done
for all participants
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determination of independent variable
for hemoglobin level. Values of
P<0.05 or less were considered
statistically significant.
Abdul-Fattah et al
shown they were 30 patients with RA
with ACD (11 males and 19 females),
with a mean±SD age of (47.1±12.6
years). Regarding the control group,
they were 10 health subjects (3 males
and 7 females) with mean±SD age of
(50.7±12.2 years). As expected, both
ESR and CRP were significantly
higher in RA group (p=0.0007 and
p=0.001 respectively).
RESULTS:
Some
of
the
baseline
characteristics and clinical and
laboratory data of both studied groups
are demonstrated in table (1). As
Table (1): Comparison between some baseline characteristics of RA group with ACD
and control group
Variable
RA group with ACD
(n=30)
47.1±12.6
Age (years)
11/19
Sex (Male/Female)
71.00±33.63
Disease Duration(months)
54.9±4.5
Morning stiffness(minutes)
2.9±1.3
No of swollen joints
50.28±24.91
ESR (mm/h)
48.52±55.72
CRP (mg/dL)
Control Group
(n=10)
50.7±12.2
3/7
17.43±7.16
4.2±0.9
P-value
0.420
1.00
NA
NA
NA
0.0007
0.001
ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein.
Comparison between some
studied hematological parameters in
RA group and control group is
demonstrated in table (2). A
significantly higher hemoglobin level
(p=0.003) and iron level (p=0.002) had
been observed in the control group
compared to RA group with ACD. On
the other hand a statistically significant
higher ferritin had been observed in
RA group patients with ACD
(p=0.011).
Table (2): Comparison between some hematological parameters of RA group with
ACD and control group
Variable
Hemoglobin(gm/dl)
RBCs (m/uL)
MCV(fl)
MCH (pg/cell)
MCHC (%)
WBC ( x109/L)
Platelets (x 109/L)
Serum iron (ug/dl)
Serum ferritin (ng/ml)
RA group with ACD Control Group
(n=30)
(n=10)
10.10±1.68
12.89±1.09
4.18±0.63
5.25±0.79
79.7±4.76
88.01±6.95
26.1±2.1
28.2±0.66
32.43±1.25
32.9±1.10
6.8±1.66
8.6±2.50
277.76±83.27
259.60±61.77
38.6±9.69
60.8±24.66
95.70±61.08
42.50±19.48
P-value
0.003
0.001
0.004
0.001
0.278
0.059
0.471
0.002
0.011
MCV: Mean corpuscular volume; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular
hemoglobin concentration.
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When
comparing
serum
prohepcidin level and TNF-α between
both groups (table 3), a statistically
significant higher levels of both had
been found in RA patients with ACD
compared to control group. Prohepcidin level in RA group with
Abdul-Fattah et al
ACD had been (292.23±103.89 ng/ml)
compared to (223.60±76.80 ng/ml) in
control group (p=0.038). Serum TNF-α
in RA group with ACD was
(78.56±35.87 pg/ml) compared to
(26.40±16.06 pg/ml) in control group
(p=0.001) (Figure 1).
Table (3): Comparison between levels of TNF-α and Pro-hepcidin between both groups
Variable
Pro-Hepcidin
(ng/mL)
TNF-α (pg/ml)
RA group with ACD
(n=30)
292.23±103.89
Control Group
(n=10)
223.60±76.80
P-value
78.56±35.87
26.40±16.06
0.001
0.038
correlation between TNF-α and
prohepcidin level had been also
observed (p=0.06) (Figure 4). Prohepcidin and TNF-α showed no
statistically significant correlation with
ESR, CRP or ferritin. No statistically
significant correlation had been
demonstrated between hemoglobin
level and CRP or ESR.
Table (4) demonstrates results
of simple linear regression analysis
between different studied parameters.
As demonstrated, Serum prohepcidin
level correlated negatively with
hemoglobin level (p=0.019) (Figure 2).
Likewise, TNF-α correlated negatively
with hemoglobin level (p=0.003)
(Figure 3). A trend towards positive
Table (4): Correlation between TNF-α & prohepcidin and some studied parameters in
RA patients with ACD
Variables
Prohepcidin Vs Hemoglobin
TNF-α Vs Hemoglobin
TNF-α Vs Prohepcidin
Prohepcidin Vs ESR
Prohepcidin Vs CRP
Prohepcidin Vs ferritin
TNF-α Vs ESR
TNF-α Vs CRP
TNF-α Vs ferritin
Hemoglobin Vs ESR
Hemoglobin Vs CRP
R
-0.452
-0.522
0.350
0.352
0.316
0.041
0.044
0.291
0.033
-0.041
-0.038
P-value
0.019
0.003
0.06
0.06
0.09
0.81
0.82
0.12
0.68
0.74
0.69
introduced in the model as the
dependent
variable
and
serum
prohepcidin, TNF-α and ferritin ESR
and CRP was an independent factors,
(Table 5).
Multivariate regression analysis of
predictors for hemoglobin in RA
patients:
On multivariate linear regression
analysis, when hemoglobin had been
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Abdul-Fattah et al
Table (5): Multivariate regression analysis of predictors of hemoglobin in RA
patients with ACD
Variable
TNF-α
Prohepcidin
Coefficient
-0.009
-0.001
Std Error
0.003
0.001
F-test
7.00
1.88
P
0.01
0.18
Figure (1): Serum Prohepcidin and TNF-α in RA patients with ACD and Control group.
350
300
250
200
150
100
50
0
TNF (pg/mL)
Prohepcidin
(ng/mL)
RA group
Control group
Figure (2): Correlation between prohepcidin level and hemoglobin levels in RA
patients with ACD.
Prohepcidin (ng/mL)
500
400
300
200
100
0
8
8.5
9
9.5
10
10.5
Hemoglobin (gm/dL)
Figure (3): Correlation between TNF-α and hemoglobin in RA patients with ACD.
180
TNF (pg/mL)
160
140
120
100
80
60
40
20
0
8
8.5
9
9.5
Hemoglobin (gm/dL)
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10.5
EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
Abdul-Fattah et al
Figure (4): Correlation between Prohepcidin and TNF-α in RA patients with ACD.
TNF (pg/mL)
200
150
100
50
0
50
150
250
350
450
550
Prohepcidin (ng/mL)
To our knowledge, this is one
of the earliest reports of assessing
serum hepcidin level in patients with
RA.
DISCUSSION:
Although anemia is not
considered to be a major problem in
rheumatoid arthritis, it is likely that
this is not the case and that this
statement is based on the fact that
studies of anemia in rheumatoid
arthritis are sparse with few systematic
reviews (Swaak, 2006).
Our finding adds to the already
sparse knowledge of the role of
hepcidin in anemia of chronic disease
and very nicely resembles several
studies addressing the problem of
anemia of chronic disease in other
conditions (Fleming, 2008). The same
finding of an increased serum prohepcidin in a group of patients with RA
had been verified in a study carried out
by Koca et al., 2008. In their series
they had documented elevated serum
prohepcidin in a cohort of RA patients
and ACD.
Anemia of chronic disease
(ACD) is one of the most common
clinical syndromes encountered in the
practice of medicine. The pathogenesis
of ACD and the regulation of iron
absorption and distribution rank among
the major unsolved problems in
classical hematology. In the last few
years rapid progress has been made on
both problems by elucidation of the
central role of hepcidin, an ironregulatory hormone and a mediator of
innate
immunity
(Weiss
and
Goodnough, 2005).
It had been shown in several
studies that hepcidin is a key regulator
for iron homeostasis in different
clinical settings.
In this study when investigating
serum prohepcidin concentration as a
marker of endogenous hepcidin levels,
we found it to be increased in patients
with RA and ACD compared to control
group. Moreover, a statistically significant negative correlation had been
found between hemoglobin level and
serum prohepcidin.
Since its discovery in 2000,
hepcidin and its role in iron
metabolism and inflammation, has
been an integral part of experimental
and clinical studies. Thereby, clinical
research has been focused on its role
on pathogenesis of anemia of chronic
disease and diseases associated with
dysregulation of iron absorption and
iron overload like hemochromatosis
(Christiansen et al., 2007).
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The role of hepcidin in iron
metabolism is increasingly being
defined (Fleming 2008; Ganz and
Nemeth, 2006 Kemna et al., 2008;
Rivera et al., 2005 and Silvestri et al.,
2008). Moreover, the role of hepcidin
had been demonstrated in a variety of
conditions associated with ACD in
infectious and inflammatory diseases
(Kemna et al., 2005; Nemeth et al.,
2003 and Theur et al 2006) and chronic
renal failure (Kato et al., 2008)
Hepcidin role had been also
demonstrated in conditions associated
with dysregulated iron metabolism as
hemaochromatosis, (Kemna et al.,
2008) and
hemoglobinopathies
(Kearney et al., 2008 and Origa et al.,
2007). Moreover, the role of hepcidin
in ACD in childhood had been also
verified in a study by Cherian et al., in
(2008). In their series they were able to
document that increased hepcidin
production is responsible for iron
accumulation in tissue macrophages
and is thought to be responsible for the
development of ACD in childhood
anemia of chronic disease in different
clinical conditions.
Abdul-Fattah et al
distribution, hepcidin might also
directly inhibit erythroid-progenitor
proliferation and survival (Howard et
al., 2007).
In our study, no statistically
significant correlation had been found
between serum porhepcidin and ferritin
level.
Conflicting reports had been
published about correlation between
pro-hepcidin and ferritin levels. So
while hepcidin has been closely
associated and positively correlated
with ferritin in some series (Dallalio et
al., 2003) and a positive correlation
was demons-trated between serum prohepcidin and ferritin levels in chronic
renal failure patients (Malyszko et al.,
2005). On the other hand Nagashima et
al., in (2006) reported that serum prohepcidin levels negatively correlated
with ferritin levels in patients with
viral hepatitis C, while this correlation
was positive in patients with viral
hepatitis B and healthy controls. Other
studies demonstrated that levels of prohepcidin were unrelated with ferritin or
other iron parameters (Roe et al., 2007
and Taes et al., 2004). These contradictory findings may support the
notion that measurement of prohepcidin with the currently available
commercial assay is not very reliable
as the substitute for bioactive hepcidin
analysis (Kemna et al., 2005 and
Tomosugi et al., 2006).
Anemia of chronic disease
typically manifests itself as a
hypoproliferative anemia accompanied
by a low serum iron concentration
despite adequate reticuloendothelial
iron stores as reflected by increased
serum ferritin (Nemeth et al., 2004). It
seems that hepcidin is the longanticipated hormone which could
explain much of the characteristics of
ACD. Findings from other studies
demonstrated that hepcidin leads to
internalization and degradation of the
iron exporter ferroportin, which is
present on the cell surface of
enterocytes attenuating iron uptake in
the gut (Nicolas et al., 2002) and
inhibits the release of iron by
macrophages (Pigeon et al., 2001). In
addition to these effects on body iron
In this series, no statistically
significant correlation had been
demonstrated between hemoglobin and
either ESR or CRP. A similar finding
had been found in other study (Peeters
et al., 1999). On the other hand, the
work by Vreugdenhil et al., in (1992)
demonstrated an association between
ACD and increased CRP and ESR. The
association between ACD and ESR
levels is more complex, as ESR
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increases independently with falling
hemoglobin levels and presence of
autoantibodies (Swaak, 2006).
Abdul-Fattah et al
exhibit low frequency and increased
apoptosis of bone marrow erythroid
progenitor and precursor cells due to
increased local production of TNF-α.
Moreover, they provided in vitro and
ex vivo evidence that TNF-α -induces
accelerated apoptosis of bone marrow
erythroid cells largely contributing to
the pathogenesis of ACD in RA.
The pathogenesis of ACD is
not purely a matter of deranged iron
metabolism,
but
also
includes
shortened red cell survival, impaired
erythropoietin production and impaired
response of erythroid progenitors to
erythropoietin
(Adamson,
2008).
Although hepcidin role in iron
metabolism had been verified, it is
more likely that other factors are also
operative.
Impaired erythropoietin production and impaired response of
erythroid progenitors to erythropoietin
are two major pathogenic mechanisms
underlying ACD. TNF-α seems to be
an ideal candidate to be a mediator in
ACD. An elegant experiment was
carried out by Faquin et al., in (1992).
In their study they had demonstrated
that when TNF-α. was added to a
human hepatoma cell line (these cells
have
the
useful
property of
upregulating
erythropoietin
gene
expression in response to hypoxia)
erythropoietin production in response
to hypoxia was dramatically reduced.
The suppressive effect of the cytokine
was dose-dependent. Similar finding
had been verified in a study by Zhai et
al., (2004). In their study they found
that in vitro recombinant TNF-α
inhibited the expression of erythropoietin mRNA in hypoxic conditions
and that the inhibitory effects became
stronger with the increase of recombinant TNF-α.
In this series a statistically
significant higher levels of TNF-α had
been documented in patients with ACD
compared to control group.
Although serum level of TNF-α had
been extensively studied in patients
with rheumatoid arthritis, this study is
additionally demonstrating a negative
correlation between this cytokine and
hemoglobin levels. Furthermore, serum
prohepcidin level positively correlated
with TNF-α level.
Previous studies have shown
that patients with rheumatoid arthritis
have increased serum concentrations of
variety of pro-inflammatory cytokines,
including TNF- (Papadaki et al.,
2002). Moreover, the role of this
cytokines in the development of ACD
has been well recognized. Increased
levels of the cytokine have been
reported in anemic patients with cancer
(Lastiri et al., 2002), parasitic and
bacterial infections (Kern et al., 1989)
and AIDS and AIDS-related complex
(Dallalio et al., 1999) in addition to
rheumatoid arthritis.
Direct evidence for the role of
TNF- in the pathogenesis of ACD in
RA has becoame available from
clinical trials using in vivo TNFblockade. Papadaki et al., in (2002)
were able to verify a beneficial effect
of administration of a TNF-α blocker
on anemia in patients with RA. In their
series, approximately 60% were
anemic and among them 65% had
ACD. After 6 doses of TNF-α blocker,
a significant improvement of hemoglobin levels was observed in the total
The
role
of
TNF
in
pathogenesis of ACD in RA patients
was verified in a series reported by
Papadiki.et al., 2002. In their series
they suggested that patients with RA
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study group compared to their baseline
values. Moreover, the most prominent
increase was obtained in the group of
ACD patients.
Abdul-Fattah et al
This
study
has
some
limitations. First, it has never been
proven that pro-hepcidin reflects level
of active-mature hepcidin. Thus, if we
measure bioactive hepcidin in serum or
urine, our results would be more
accurate, a finding that had been
supported by other investigators
(Kemna et al., 2005 and Tomosugi et
al., 2006).
It seems that TNF-α may also
play a role in the disturbance of iron
metabolism in patients with ACD.
Laftah et al., (2006) demonstrated that
TNF-α stimulation results in upregulation of cellular iron import
protein
DMT1 (divalent
metal
transporter 1) and reduced the iron
exporter IREG1 (iron-regulated protein
1) in a human monocyte cell line.
These actions were found to be
independent of hepcidin.
In inflammatory diseases, iron
deficiency anemia can coexist with
ACD due to poor intake and/or
absorption and increased loss of iron,
and so, to differentiate between ACD
and iron deficiency anemia may be
difficult. The most reliable tool for
detecting iron deficiency is stainable
iron content in bone marrow aspirate.
Recently, serum transferrin receptor
level was proposed as a sensitive
characteristic for detection of iron
deficiency (Swaak, 2006). Thus, our
failure to use more sensitive indicators
such as transferrin receptor to exclude
iron deficiency anemia may be another
limitation of the present study.
In the present study, serum
TNF-α plasma levels correlated
positively with serum prohepcidin, also
both correlated negatively with
hemoglobin level. This may imply a
cause effect relationship between TNFα and hepcidin production.
The mechanism leading to
increased hepcidin in patients with
rheumatoid arthritis can be attributed
to chronic inflammation. RA is best
described as a chronic inflammatory
condition. RA is associated with
deranged cytokine including, among
others, IL-6, IL-1 and TNF-α.
In summary, we have shown
that both hepcidin and TNF- α play an
important role in the development of
ACD in patients with RA. Moreover, it
seems that there is some sort of
synergism between both. However,
these findings require confirmation in
larger cohort of patients. Data from
this study may have implications in the
understanding the mechanisms of ACD
associated not only with RA but also
with other chronic inflammatory
diseases.
Although, Nemeth et al., in
2003 had found that hepcidin mRNA
was induced by interleukin-6 in vitro,
but not by TNF- , a more recent report
found that TNF-α, which is produced
mainly by activated macrophages in
patients with RA is capable of inducing
the production of other cytokines
including IL-6 which is a major
inducer for hepcidin release. In this
series the author implicated TNFalso in direct induction of hepcidin
expression (Brennan and McInnes,
2008).
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‫‪EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008‬‬
‫فقر دم األمراض المزمنة في مرض الروماتويد المفصلي دور محتمل لهرمون‬
‫الهيبسيدين وعامل النخر الورمي – الفا‬
‫محمد عماد عبد الفتاح* – ايمن جميل غبلاير** – عبده اللبان‪ - $‬أحمد عبد الناصر‬
‫‪$‬‬
‫أقسام أمراض الباطنة العامة* و الباثولوجيا االكلنيكي** واالروماتيزم والتأهيل‬
‫كلية الطب – جامعة المنيا‬
‫‪$‬‬
‫مر ا رو امويا رد رومفصر م مررم رضمر را ر ر مل ابررح روًررمن يمد رردر امررم ررمم‬
‫أع ر ه مداث بق دم رضم را رومزمنح‪ .‬لن ه مام روه مً د م دا ر هومو بم مرداث بقر‬
‫دم رضمر را رومزمنررح بررم ن ر مررم رضمر را اونررم هررمر روه مررام وررم يرريم د رًرريه بررم مر ا‬
‫رو امويا د رومفص م‪ .‬عومل رونخ روا مم‪ -‬روفو ها رضخ مدا أنه لرن دا ر هومرو برم مرداث‬
‫بق دم رضم را رومزمنح ‪.‬‬
‫اقد أج ي همر روممث مغ ا يق م دا روه مً د م ا عومل رونخر رورا مم روفرو برم مرداث‬
‫بق دم رضم را رومزمنح بم م ا رو امويا د رومفص م‪.‬‬
‫ررو لررونام مررم بق ر دم رضم ر را رومزمنررح‬
‫اقررد أج رره هررما رود رًررح ع ر عرردد ‪ 30‬م‬
‫رومصومام موو امويا د رومفص م اقرد يرم ق روس نًرمح ه مرام روه مًر د م مووردم نرمو عومرل‬
‫رونخ روا مم‪ -‬أوفو‪.‬‬
‫اقد أظه ه رونيوئج ر يفوع ما دالوح إمصوئ ح ونل مم ه مام روه مً د م ا عومل رونخ‬
‫روررا مم روفررو بم نمررو نرروم مياًرري روه مًر د م ‪103.89 ± 292.23‬نررونا جر رم‪ /‬مررل) بررم‬
‫م ر ا رو امويا رد رومفص ر م ن روم هررمر رومياًرري ‪ 76.80 ± 23.6‬نررونا ج ر رم‪ /‬مررل) بررم‬
‫رومجماعح رو وميح‪ .‬أمو موونًمح ولومل رونخ روا مم روفو نوم رومياًي ‪35.78 ± 78.56‬‬
‫م نررا رر رم ‪ /‬مررل) ممجماعررح رو امويا رد رومفصر م انرروم هررمر رومياًرري ‪16.06 ±26.40‬‬
‫م نا ر رم ‪ /‬مل) بم رومجماعح رو وميح‪ .‬اقد أظه ه رونيروئج أ رو عةقرح ًر م ح مر م نرل‬
‫مم ه مام روه مً د م اعومل رونخ روا مم روفو انًمح روه ماج ام م موودم‪.‬‬
‫منوء ع ر نيروئج هرما رود رًرح نًريي ن أم نًرينيج أم نرل مرم مًريا روه مًر د م روردم‬
‫انمو عومل رونخ رورا مم روفرو وهرم دا أًوًرم برم مرداث رن م رو رضمر را رومزمنرح برم‬
‫م ا رو امويا د رومفص م ‪.‬‬
‫‪337‬‬