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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 38  |  Issue : 1  |  Page : 23-28

Growth differentiation factor 15 expression in anemia of chronic disease and iron deficiency anemia


Department of Clinical Pathology, Hematology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission01-Oct-2012
Date of Acceptance16-Jun-2012
Date of Web Publication20-Jun-2014

Correspondence Address:
Deena M.M. Habashy
Department of Clinical Pathology, Hematology Unit, Faculty of Medicine, Ain Shams University, 11566 Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJH.0000423012.78137.2e

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  Abstract 

Background

Growth differentiation factor 15 (GDF15) expression, at the high levels achieved in the setting of ineffective erythropoiesis, contributes toward pathological iron overloading through a mechanism of incomplete hepcidin suppression. In addition to the regulation of hepcidin, iron depletion or chelation in the host may regulate GDF15 expression.

Objectives

This study aimed to detect GDF15 expression in Egyptian patients with iron deficiency anemia (IDA) and anemia of chronic disease (ACD) to examine its possible role in their differentiation.

Patients and methods

GDF15 was detected using an enzyme-linked immunosorbent assay in 40 patients (20 with IDA and 20 with ACD) and 10 age-matched and sex-matched healthy controls.

Results

The IDA group showed a decrease in the mean values of hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), serum iron and ferritin, and higher total iron-binding capacity (TIBC) compared with the controls (P⩽0.001). The ACD group had a statistically significantly higher mean value of GDF15 than the control and IDA groups (P⩽0.001). The mean values of Hb, MCV, serum iron, and TIBC were statistically significantly lower, with higher serum ferritin in the ACD group compared with the controls (P⩽0.001, P=0.01, P⩽0.001, P⩽0.001, and P=0.004, respectively). Higher mean values of MCV, MCH, and ferritin were found in the ACD compared with the IDA groups (P⩽0.001), whereas TIBC was higher in the IDA group compared with the ACD groups (P⩽0.001). No statistically significant correlation was found between the serum GDF15 level and the laboratory data studied among the ACD and IDA groups (P>0.05). No difference was found between serum C-reactive protein-positive and serum C-reactive protein-negative ACD groups in the laboratory parameters studied (P>0.05).

Conclusion

GDF15 plays an important role in the pathogenesis of ACD and IDA, and it can be used as a potential marker in their differentiation. Although GDF15 is linked to iron homeostasis in IDA, its increased concentrations in ACD are mostly because of inflammation.

Keywords: anemia of chronic disease, growth differentiation factor 15, iron deficiency anemia


How to cite this article:
Abaza HM, Habashy DM, El-Nashar RE. Growth differentiation factor 15 expression in anemia of chronic disease and iron deficiency anemia. Egypt J Haematol 2013;38:23-8

How to cite this URL:
Abaza HM, Habashy DM, El-Nashar RE. Growth differentiation factor 15 expression in anemia of chronic disease and iron deficiency anemia. Egypt J Haematol [serial online] 2013 [cited 2019 Dec 14];38:23-8. Available from: http://www.ehj.eg.net/text.asp?2013/38/1/23/134799


  Introduction Top


Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-β (TGF-β) superfamily. It has been identified as a hypoxia-inducible gene product and as a molecule involved in hepcidin regulation 1. The GDF15 is synthesized as a precursor protein that undergoes disulfide-linked dimerization like TGF-β. The precursor form mediates binding to the extracellular matrix, creating a latent stromal stock of proGDF15. The precursor protein is cleaved to form the mature C-terminal GDF15 peptide, which is subsequently secreted as a 25–30 kDa dimer 2.

The GDF15 is one of the major secreted proteins induced by the tumor suppressor protein p53 3. Several studies suggest that GDF15 induction is associated with cell-cycle arrest and apoptosis 4. Hence, GDF15 may be an excellent in-vivo biomarker of the p53 pathway activation 5.

The GDF15 expression during late erythroid differentiation was discovered as a part of an erythroblast transcriptome project 6. Although GDF15 expression is associated with cellular stress or apoptosis, this hormone is a prerequisite for normal erythroid differentiation 1. Moreover, the GDF15 is involved in ineffective erythropoiesis 6, being strongly increased in β-thalassemia and congenital dyserythropoietic anemia. The cytokine blocks hepcidin expression and increases iron absorption, thus leading to iron loading in these anemias 7.

As intracellular iron availability affects GDF15 expression 1, recent studies have examined the potential pathophysiological role of GDF15 in anemia of chronic disease (ACD) and iron deficiency anemia (IDA). Moreover, detection of the association of GDF15 expression with serum iron parameters in patients with IDA and ACD may be helpful for determination of the diagnostic and pathogenic impact of GDF15 in these anemias 8.

ACD is a common clinical problem complicating diseases involving acute and chronic immune activation, such as infections, malignancies, or autoimmune disorders 9. The circulating concentrations of the GDF15 are significantly increased in ACD, most likely as a consequence of inflammation; however, its pathophysiological role has not yet been elucidated 8.

IDA affects billions of individuals worldwide. It develops when iron stores become insufficient to maintain normal erythropoiesis 10. Iron depletion increases GDF15 expression 1. Although GDF15 is probably linked to the degree of anemia, the need for erythropoiesis, and iron homeostasis in IDA, the role of GDF15 in IDA is still controversial 8.


  Aim of the work Top


This study aimed to detect GDF15 expression in Egyptian patients with IDA and ACD to examine its possible role in their differentiation.


  Patients and methods Top


Patients

This study was carried out on 40 patients: 20 patients with IDA and 20 patients with ACD, who were admitted to Ain Shams University Hospitals, during the years 2011–2012. They were diagnosed by a complete blood count and iron profile. The IDA group included seven men (35%) and 13 women (65%), with a male to female ratio of 1 : 1.9; their ages ranged from 19 to 82 years (mean: 48.2±17.8 years). Meanwhile, in the ACD group, there were nine men (45%) and 11 women (55%), with a male to female ratio of 1 : 1.2; their ages ranged from 20 to 70 years (mean: 53.1±13.9 years).

Ten healthy age-matched and sex-matched individuals served as a control group: four men (40%) and six women (60%), with a male to female ratio 1 : 1.5; their ages ranged from 23 to 71 years (mean: 48.2±15.4 years). All individuals in the control group were free from any other condition that may affect the serum GDF15 level, such as inflammation. All participants were informed about the objectives and procedures of the study, and provided written consent.

Methods

Sampling


Six milliliters of peripheral blood was withdrawn aseptically from all the patients and controls studied, and was divided as follows:

  1. Two milliliters was added to EDTA-coated vacutainer tubes for the complete blood count.
  2. Four milliliters was added to plain tubes to obtain sera. Two milliliters was used to determine the iron profile [serum iron, ferritin, and total iron-binding capacity (TIBC)] and C-reactive protein (CRP). The remaining 2 ml was used to perform an enzyme-linked immunosorbent assay (ELISA) for the detection of serum GDF15.


Iron profile assays

Serum iron: Principle: Iron reagent is used to measure the iron concentration using a timed end-point method. In the reaction, iron is released from transferrin by acetic acid and is reduced to its ferrous state by hydroxylamine and thioglycate. The ferrous ion is immediately complexed with ferrous zinc plus iron reagent. The Synchron CX system (Beckman Coulter, Hialeah, Florida, USA) automatically divides the appropriate sample and reagent volumes into a cuvette. The ratio used is one part sample to eight parts reagent. The system monitors the change in the absorbance at 560 nm. This change in the absorbance is directly proportional to the concentration of iron in the sample, and is used by the Synchron CX system to calculate and express the iron concentration 11.

Ferritin: Sandwich principle:

  1. First incubation: 10 μl of sample, a biotinylated monoclonal ferritin-specific antibody, and monoclonal ferritin-specific antibody labeled with a ruthenium complex form a sandwich complex.
  2. Second incubation: after the addition of streptavidin-coated microparticles, the complex becomes bound to the solid phase through the interaction of biotin and streptavidin.
  3. The reaction mixture is aspirated into the measuring cell, where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed. Application of a voltage to the electrode then induces chemiluminescent emission, which is measured by a photomultiplier.
  4. Results are determined using a calibration curve that is instrument-specifically generated by 2-point calibration and a master curve provided through a reagent barcode 11.


TIBC: Principle: For iron, ferric ions are released from transferrin by guanidine hydrochloride and reduced to a ferrous state by hydroxylamine. Ferrous ions react with ferrozine, forming a colored complex. The intensity of the color is directly proportional to the iron concentration and is determined by monitoring the increase in absorbance at 546 nm.

For TIBC, the transferrin in the specimen is saturated with iron by exposure to excess ferric ions; then, unbound iron is removed by the addition of light magnesium carbonate and centrifugation. The iron bound to protein in the supernatant is measured by the principle applied to total iron, as described above 11.

CRP assay

Principle: It is a rapid latex agglutination test, using the AVITEX CRP kit (Omega diagnostics Alva FK12 5DQ; Omega Diagnostics Ltd, Scotland, UK), in which the particles are coated with antibodies to human CRP. When the latex suspension is mixed with serum containing elevated CRP levels on a slide, clear agglutination is observed within 2 min 12.

GDF15 assay

The detection of GDF15 serum level was carried out using ‘Quantikine human GDF15 ELISA’ (R&D Systems, Minneapolis, Minnesota, USA) following the manufacturer’s protocol. This assay uses the quantitative sandwich enzyme immunoassay technique. A monoclonal antibody specific for GDF15 is precoated onto a microplate. Standards and samples were pipetted into the wells and any GDF15 present was bound by the immobilized antibody. After washing away any unbound substances, an enzyme-linked polyclonal antibody specific for GDF15 was added to the wells. Following a wash to remove any unbound antibody-enzyme reagent, a substrate solution was added to the wells, and color developed in proportion to the amount of GDF15 bound in the initial step. The color development was stopped and the intensity of the color was measured.

Calculation of results

A standard curve using the logarithmic scale was constructed by plotting the mean absorbance, for each standard, on the y-axis against the concentration on the x-axis and a best-fit curve was drawn through the points on the graph. As serum samples have been diluted, the concentration read from the standard curve was multiplied by the dilution factor. The serum GDF15 reference range was considered to be between 0.33 and 1.06 ng/ml according to the Quantikine human GDF15 ELISA kit.

Statistical analysis

IBM SPSS statistics (2011, version 20.0; IBM Corp., Armonk, New York, USA) was used for data analysis. Data were expressed as mean±SD (X±SD) for quantitative parametric measures and both number and percentage for categorized data. A comparison of two independent mean groups for parametric data was carried out using the Student t-test (t) and the Mann–Whitney U-test (Z value) for comparisons between two independent samples with a nonparametric distribution. The ranked Spearman correlation test (r) was used to study the possible association between two variables in each group for nonparametric data. The P value less than 0.05 was considered the cut-off value for significance.


  Results Top


The mean values of hemoglobin (Hb), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were significantly decreased in the IDA group (10.1±1.6 g/dl, 71.3±4.1 fl, and 23.3±1.7 pg, respectively) compared with the control group (13.5±1.1 g/dl, 89.5±3.8 fl, and 29.8±1.5 pg, respectively) (P⩽0.001) [Table 1]. In terms of the serum iron profile, the mean levels of serum iron and ferritin showed a statistically highly significant decrease in the IDA group (35.5±11.6 µg/dl and 8.05±1.4 ng/ml, respectively) compared with the control group (98.7±20.3 µg/dl and 110.6±57.6 ng/ml, respectively) (P⩽0.001) [Table 1]. Meanwhile, the mean value of TIBC was higher in the IDA group (520.85±41.4 µg/dl) compared with the control group (361.5±62.6 µg/dl) (P⩽0.001) [Table 1]. No significant difference was found between the IDA and the control groups in serum GDF15 expression (P=0.17; [Table 1] and [Figure 1].
Table 1: Comparison of laboratory parameters of the IDA group vs. controls

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Figure 1: GDF15 levels in ACD, IDA, and control groups. ACD, anemia of chronic disease; GDF15, growth differentiation factor 15; IDA, iron deficiency anemia.

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The mean values of Hb and MCV were statistically significantly lower in the ACD group (9.3±1.3 g/dl and 85.15±5.3 fl, respectively) compared with the control group (13.52±1.08 g/dl and 89.5±3.8 fl, respectively) (P⩽0.001 and P=0.01, respectively) [Table 2]. Also, the mean level of serum iron and TIBC showed a statistically highly significant decrease in the ACD group (31.4±3.02 and 256.6±7.5 µg/dl, respectively) compared with the control group (98.7±20.3 and 361.5±62.6 µg/dl, respectively) (P⩽0.001). Meanwhile, a higher mean value of serum ferritin was found in the ACD group (185.9±42.6 ng/ml) compared with the control group (110.6±57.6 ng/ml) (P⩽0.01) [Table 2]. In terms of serum GDF15 expression, the ACD group showed a higher mean value (3.361±1.6 ng/ml) compared with the control group (0.52±0.19ng/ml) (P⩽0.001) [Table 2] and [Figure 1]
Table 2: Comparison between laboratory parameters of the ACD group vs. controls

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On comparing IDA and ACD groups, higher mean values of MCV, MCH, and ferritin were found in the ACD group (85.15±5.3 fl, 28.85±2.1 pg, and 185.9±42.6 ng/ml, respectively) compared with the IDA group (71.25±4.1 fl, 23.3±1.7 pg, and 8.05±1.4 ng/ml, respectively) (P⩽0.001) [Table 3], whereas the mean value of TIBC was higher in the IDA group (520.85±41.4 µg/dl) compared with the ACD group (185.9±42.6 µg/dl) (P⩽0.001) [Table 3]. In terms of serum GDF15 expression, the ACD group showed a higher mean value (3.361±1.6 ng/ml) compared with the IDA group (0.42±0.219 ng/ml) (P⩽0.001) [Table 3] and [Figure 1].
Table 3: Comparison of laboratory parameters of the IDA group and the ACD group

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No correlation was found between the serum GDF15 level and the laboratory parameters studied among the ACD and IDA groups (P>0.05) [Table 4] and [Table 5]. In the ACD group, the laboratory data studied showed no significant difference between CRP-positive (n=12) and CRP-negative (n=8) cases (P>0.05) [Table 6].
Table 4: Correlation between GDF15 and the laboratory parameters studied in the IDA group

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Table 5: Correlation between GDF15 and the laboratory parameters studied in the ACD group

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Table 6: Comparison of the laboratory parameters studied of CRP-positive ACD vs. CRP-negative ACD patients

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  Discussion Top


The GDF15 is produced in erythroid precursor cells to signal iron demand for erythropoiesis and regulate hepcidin expression 13. The GDF15 was recently investigated as a marker of ineffective erythropoiesis in several anemias 14. On the basis of the vast expansion of medullary and extramedullary erythropoiesis, the erythroblast demand for iron is huge. There is a clear increase in iron kinetics, tissue hypoxia, and erythropoietin in these patients, which act together with other physiological mechanisms to suppress hepcidin and meet the erythroblast demand for iron. Once the host tissues load enough iron to meet the erythroblast demand, hepcidin expression should increase to levels sufficient for prevention of tissue iron overloading. Instead, hepcidin expression remains within the normal range, partially because of overexpression of GDF15 6. We aimed to detect GDF15 expression in IDA and ACD to elucidate its possible role in their diagnosis.

In this study, on comparing the serum iron profile among IDA and controls, the results showed a statistically significant decrease in the levels of serum iron and ferritin associated with a significant increase in the serum TIBC among IDA patients [Table 1]. This was in agreement with the study of Theurl et al. 15.

In terms of the serum iron profile among the ACD patients, the present study found a statistically highly significant increase in the levels of serum ferritin in the ACD patients compared with the control and IDA groups [Table 2] and [Table 3], respectively). Similarly, Weiss and Goodnough 9 reported an increase in the level of serum ferritin in patients with ACD.

The present results showed that IDA and ACD patients had statistically significant lower Hb levels than the healthy controls [Table 1] and [Table 2]. This was also supported by Cheng et al. 16, who found decreased Hb levels in IDA and ACD groups compared with healthy controls.

In terms of the RBC indices (MCV and MCH), the present results indicated that patients of the IDA group had statistically significantly lower MCV and MCH levels than the controls and ACD patients [Table 1] and [Table 3], respectively). In accordance, IDA patients were previously presented with microcytic hypochromic anemia 17; meanwhile, ACD patients had normal levels of MCV and MCH 16.

In terms of the serum GDF15 level, the present study found no statistically significant difference between IDA patients and controls [Table 1]. In contrast, Theurl et al. 8 documented a decrease in the level of serum GDF15 in the IDA group, whereas Lakhal et al. 1 reported that iron depletion increases GDF15 expression in cultured cells, and that iron chelation causes a transient increase in GDF15 levels among human research participants. The same study also reported significant elevations in GDF15 among randomly chosen patients with iron deficiency, but other etiologies for increased GDF15 were not explored.

The present results also found the presence of a statistically highly significant increase in the serum level of GDF15 in ACD patients in comparison with the controls [Table 2] and [Figure 1]. This was in agreement with the study of Theurl et al. 8. The proinflammatory and anti-inflammatory cytokines play an important role in the pathophysiology of ACD by increasing iron accumulation and storage in monocytes/macrophages through the hepcidin-dependent pathway 18 The GDF15 has been shown to suppress hepcidin in patients with hepatocellular iron overload and anemia 13 In contrast to iron-loading anemias, ACD is associated with reduced duodenal iron absorption and macrophage iron retention 9.

In this work, a statistically highly significant increase in the mean value of GDF15 level was found in the ACD group versus the IDA group [Table 3] and [Figure 1]. This was in agreement with a previous report detecting a higher serum GDF15 level in ACD patients compared with those with IDA 8. This indicates the value of serum GDF15 in the differentiation between IDA and ACD. The increase in the serum GDF15 level among ACD patients was attributed to inflammation, because ACD patients have significantly higher concentrations of interleukin-6 (IL-6), IL-1b, and CRP than IDA patients who have comparable Hb levels 8. However, Ramirez et al. 19 suggested that it may be related to the fact that erythroid cells from ACD patients secrete a GDF15-specific stimulator that is not induced in IDA.

On correlating the GDF15 level with the levels of Hb, MCV, and MCH in the IDA and ACD groups in the present work, no statistically significant correlation was found between serum GDF15 and any of the three parameters in the IDA and ACD groups [Table 4] and [Table 5]. This was in contrast with Theurl et al. 8, who reported that GDF15 was correlated negatively to the Hb concentration in IDA patients.

On correlating the GDF15 levels and the iron profile (levels of iron, ferritin, and TIBC) in IDA and ACD patients, the present study found a nonsignificant correlation between serum GDF15 and any of the three parameters [Table 4] and [Table 5]. The absence of a statistically significant correlation between serum GDF15 and serum ferritin among these groups has been reported previously 8.

For CRP, the present results showed that ACD patients with positive CRP had lower GDF15 levels than ACD patients with negative CRP. This difference was statistically nonsignificant [Table 6]. No significant correlation was found between GDF15 and CRP in a previous work in ACD patients 8.


  Conclusion Top


The current study suggests that GDF15 may play an important role in the pathogenesis of ACD and IDA, and can be used as a potential marker for the differentiation of ACD from IDA. Although GDF15 is linked to the need for erythropoiesis and iron homeostasis in IDA, the significantly increased circulating concentrations of this protein in ACD are, most likely, a result of inflammation. Further studies correlating the plasma levels of various inflammatory cytokines (especially IL-6 and IL-1β) to the expression of GDF15 in ACD, to explore their role in ACD, are recommended. Also, measurement of serum GDF15 in anemia of various etiologies should be carried out to examine a putative role of GDF15 in the pathogenesis and differential diagnosis of these anemias.

Acknowledgements

The facilities offered by the Department of Clinical Pathology, Hematology Unit, Ain Shams University, to carry out this work are greatly appreciated.[19]

 
  References Top

1.Lakhal S, Talbot NP, Crosby A, Stoepker C, Townsend AR, Robbins PA, et al. Regulation of growth differentiation factor 15 expression by intracellular iron. Blood. 2009;113:1555–1563  Back to cited text no. 1
    
2.Fairlie WD, Zhang H, Brown PK, Russell PK, Bauskin AR, Breit SN. Expression of a TGF-beta superfamily protein, macrophage inhibitory cytokine-1, in the yeast Pichia pastoris. Gene. 2000;254:67–76  Back to cited text no. 2
    
3.Tan M, Wang Y, Guan K, Sun Y. PTGF-beta, a type beta transforming growth factor (TGF-beta) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-beta signaling pathway. Proc Natl Acad Sci USA. 2000;97:109–114  Back to cited text no. 3
    
4.Bauskin AR, Brown DA, Kuffner T, Johnen H, Luo XW, Hunter M, Breit SN. Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer. Cancer Res. 2006;66:4983–4986  Back to cited text no. 4
    
5.Yang H, Filipovic Z, Brown D, Breit SN, Vassilev LT. Macrophage inhibitory cytokine-1: a novel biomarker for p53 pathway activation. Mol Cancer Ther. 2003;2:1023–1029  Back to cited text no. 5
    
6.Tanno T, Noel P, Miller JL. Growth differentiation factor15 in erythroid health and disease. Curr Opin Hematol. 2010;17:184–190  Back to cited text no. 6
    
7.Tamary H, Shalev H, Perez-Avraham G, Zoldan M, Levi I, Swinkels DW, et al. Elevated growth differentiation factor 15 expression in patients with congenital dyserythropoietic anemia type I. Blood. 2008;112:5241–5244  Back to cited text no. 7
    
8.Theurl I, Finkenstedt A, Schroll A, Nairz M, Sonnweber T, Bellmann-Weiler R, et al. Growth differentiation factor 15 in anemia of chronic disease, iron deficiency anemia and mixed type anemia. Br J Haematol. 2009;148:449–455  Back to cited text no. 8
    
9.Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–1023  Back to cited text no. 9
    
10.Tanno T, Rabel A, Lee T, Yau Y, Leitman S, Miller J. Expression of growth differentiation factor 15 is not elevated in individuals with iron deficiency secondary to volunteer blood donation. Transfusion. 2010;50:1532–1535  Back to cited text no. 10
    
11.Worwood M, May ABain BJ, Bates I, Laffan MA, Lewis SM. Iron deficiency anemia and iron overload: methods for assessing iron status. Dacie and lewis practical haematology. 201211th ed. UK ElSevier Churchill Livingstone:179–180  Back to cited text no. 11
    
12.Hind CRH, Pepys MB. The role of serum C-reactive (CRP) measurement in clinical practice. Int Med. 1984;5:112–151  Back to cited text no. 12
    
13.Tanno T, Bhanu NV, Oneal PA, Goh S, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13:1096–1101  Back to cited text no. 13
    
14.Musallam KM, Taher AT, Duca L, Claudia Cesaretti C, Halawi R, Cappellini MD. Levels of growth differentiation factor-15 are high and correlate with clinical severity in transfusion-independent patients with β thalassemia intermedia. Blood Cells Mol Dis. 2011;150:486–489  Back to cited text no. 14
    
15.Theurl FH, Urban JE, Keffer JE. Discriminating between iron deficiency anemia and anemia of chronic disorders using traditional indices of iron status versus transferrin receptor concentration. Clin Pathol. 2001;115:112–118  Back to cited text no. 15
    
16.Cheng PP, Jiao X, Wang X. Hepcidin expression in anemia of chronic disease and concomitant iron deficiency anemia. Clin Exp Med. 2010;11:33–42  Back to cited text no. 16
    
17.Pasricha SS, Flecknoe-Brown SC, Allen KJ, Gibson PR, McMahon LP, Olynyk JK, et al. Diagnosis and management of IDA: a clinical update. Med J Aust. 2010;193:525–532  Back to cited text no. 17
    
18.Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. 2002;100:3776–3781  Back to cited text no. 18
    
19.Ramirez JM, Schaad O, Durual S, Cossali D, Docquier M, Beris P, et al. Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring sideroblasts. Br J Haematol. 2009;144:251–262  Back to cited text no. 19
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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