ORIGINAL ARTICLE Year : 2021  |  Volume : 46  |  Issue : 2  |  Page : 123-132

The relationship of serum growth differentiating factor 15 with hepcidin in posttransplant adult Egyptian patients and its prognostic significance

Mostafa K.H ElRazzaz, Mohamed O Azzazi, Amal M AlAfifi, Hany M. Abd-Allah Hegab, Amro M.S El-Ghammaz, Mohammad Abd-Allah Shazly MD 
Department of Internal Medicine and Haematology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission29-Jan-2021Date of Acceptance12-Feb-2021Date of Web Publication29-Oct-2021

Correspondence Address:
Mohammad Abd-Allah Shazly
Department of Internal Medicine, Hematology and BMT Unit, Ain Shams University, Cairo, 1199
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ejh.ejh_12_21

Background Hepcidin is a small peptide that is produced in the liver that is most likely the major regulator of iron. Based upon the importance of iron, multiple mechanisms exist for the regulation of hepcidin. Iron levels, inflammation, erythropoiesis, and the combined effects of several proteins expressed on hepatocyte membranes are involved. Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-b. GDF15 expression level is usually low in resting cells but may be substantially increased following response to diverse cellular stress signals, such as hypoxia, inflammation, acute tissue injury, and during cancer progression.
Aim The aim was to assess the relationship of serum GDF15 with hepcidin in posttransplant adult Egyptian patients as an assessment for iron overload and their relationship with posttransplantation complications.
Patients and methods Serum GDF15 and hepcidin were measured using enzyme-linked immunosorbent assay in 45 postallogenic (23 patients) and autologous (22 patients) bone marrow transplanted patients 1 year after transplantation in comparison with 15 healthy controls recruited from the bone marrow transplantation unit, Ain Shams University Hospitals.
Results Serum level of GDF15 and hepcidin level were elevated 1 year after allogenic and autologous transplantation patients in comparison with control group, with a statistically significant difference between patients and controls (P<0.001). GDF15 and hepcidin were positively correlated with ferritin level (P<0.001). GDF15 and ferritin were positively correlated with acute graft-versus-host disease (GVHD) and chronic GVHD (P=0.004 and 0.002, respectively), but hepcidin did not show any significant correlation with acute GVHD (P=0.110). Moreover, GDF15, hepcidin and ferritin were positively correlated with serum levels of alanine transferase and aspartate transferase in both autologous and allogenic transplanted patients. However, GDF15, hepcidin, and ferritin were not correlated with bacterial or viral infections in both allogenic and autologous groups of patients.
Conclusion Both GDF15 and hepcidin are useful biomarkers for iron overload in late postallogenic and autologous bone marrow transplantation, and both can be used as a predictor for posttransplantation complications.

Keywords: bone marrow transplantation, ferritin, growth differentiation factor 15, hepcidin, iron overload

How to cite this article:
ElRazzaz MK, Azzazi MO, AlAfifi AM, Hegab HM, El-Ghammaz AM, Shazly MA. The relationship of serum growth differentiating factor 15 with hepcidin in posttransplant adult Egyptian patients and its prognostic significance. Egypt J Haematol 2021;46:123-32
How to cite this URL:
ElRazzaz MK, Azzazi MO, AlAfifi AM, Hegab HM, El-Ghammaz AM, Shazly MA. The relationship of serum growth differentiating factor 15 with hepcidin in posttransplant adult Egyptian patients and its prognostic significance. Egypt J Haematol [serial online] 2021 [cited 2021 Oct 30];46:123-32. Available from: http://www.ehj.eg.net/text.asp?2021/46/2/123/329505   Introduction 

Hematopoietic stem cell transplantation (HSCT) is an established treatment modality with a curative potential in a variety of hematological disorders. Although remarkable advances in transplant immunology and supportive care allowed widespread use of HSCT, transplant-related morbidity and mortality remain as a problem [1].

There are two types of SCT: first, there is autologous SCT, in which stem cells previously collected from the patients are given back after undergoing high-dose chemotherapy as a ‘stem cell rescue,’ and second, allogeneic SCT is a procedure in which mobilized stem cells from a healthy donor are given to a patient to evoke an immune response in the patient to cure a hematological cancer [2].

Iron overload (IO) is a relatively common condition in patients with hematological malignancies and HSCT recipients. Free iron which accompanies IO might contribute to the already existing prooxidant state in HSCT recipients by inducing the formation of reactive oxygen species. Tissue peroxidation and organ damage, as a consequence, contribute to the development of some early transplant complications [3].

Hepcidin is a small peptide that is produced in the liver that is most likely the major regulator of iron. It acts by causing the endocytosis and degradation of ferroprotein. Based upon the importance of iron, multiple mechanisms exist for the regulation of hepcidin. Iron levels, inflammation, erythropoiesis, and the combined effects of several proteins expressed on hepatocyte membranes are involved [4].

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-b superfamily [5]. GDF15 expression level is usually low in resting cells but may be substantially increased following response to diverse cellular stress signals, such as hypoxia, inflammation, short wave length light exposure, acute tissue injury, and during cancer progression [6].

  Aim 

The aim was to assess the relationship of serum GDF15 with hepcidin in posttransplant adult Egyptian patients as an assessment for IO and their relationship with posttransplantation complications.

  Patients and methods 

This is a case–control study that was conducted on adult patients after bone marrow transplantation who were recruited from the clinical hematology, oncology, and bone marrow transplantation unit of Ain Shams University hospital (Cairo, Egypt) over the period from August 2018 to August 2019. A total of 45 adult patients who had bone marrow transplantation (both autologous and allogenic) for more than 1 year were enrolled in this study and followed up for 1 year; besides, 15 age-matched and sex-matched healthy controls were included in the study.

The study was done in accordance with the ethical standards of the Ethics Committee of Faculty of Medicine, Ain Shams University, and with the 1975 Helsinki Declaration as revised in 1983. Informed consent was obtained from all individual participants included in the study.

The patients were divided into two subgroups:

Group 1: it included 22 patients, comprising 11 patients with multiple myeloma, six patients with non-Hodgkin disease and five patients with Hodgkin disease (HD), who underwent autologous bone marrow transplantation. Patients with multiple myeloma received melphalan as a conditioning regimen, whereas patients with Hodgkin disease and non-Hodgkin disease received LEAM protocol. LEAM is formed of lomustine, cytarabine, etoposide, and melphalan.Group 2: it included 23 patients, comprising 10 patients with acute lymphoblastic leukemia and 13 patients with acute myeloid leukemia, who underwent allogenic bone marrow. Patients with acute lymphoblastic leukemia received TBI/CYC and patients with acute myeloid leukemia received BU/FLU. TBI/CYC is formed of total body irradiation and cyclophosphamide. BU/FLU is formed of busulfan and fludarabine.

Exclusion criteria

The following were the exclusion criteria:

Patients with myelodysplastic syndromes, aplastic anemia, and thalassemias.Patients with chronic infections, other malignancies, and severe comorbidities.Patient with iron-deficiency anemia.

All participants underwent full history taking, thorough physical examination, complete blood picture, blood chemistry [including liver and kidney function tests, serum electrolytes, and lactate dehydrogenase (LDH)], iron profile including serum iron, ferritin, and total iron-binding capacity, as well as assessment of expression of GDF15 in serum of the adult patients after transplantation using enzyme-linked immunosorbent assay in comparison with serum hepcidin level using enzyme-linked immunosorbent assay.

Statistical methodology

Analysis of data was done by IBM computer using SPSS (2009; IBM, USA) (the Statistical Program for Social Sciences), version 20.0 as follows:

Description of quantitative variables as mean, SD, range, median, and interquartile range.Description of qualitative variables as number and percentage.χ2 test was used to compare qualitative variables between groups.Independent t test was used to compare the means of two independent groups to determine whether there is a statistical evidence that the associated population means are significantly different.Mann–Whitney test was used to compare difference between two independent groups when the dependent variables are not normally distributed.Pearson’s correlation coefficient (r) test was used for correlating data.Kruskal–Wallis test was used to determine if there are statistically significant differences between two or more groups of an independent variables.

P value greater than 0.05 was considered insignificant, P value less than 0.05 was considered significant, and P value less than 0.01 was considered highly significant.

  Results 

When comparing between the mean level of both GDF15 and hepcidin in transplanted patients and control group, there were a statistically significant difference (P<0.001) ([Table 1]). Moreover, there was a statistically significant difference when comparing between both autologous and allogenic groups regarding the mean levels of GDF15, hepcidin, and ferritin (P<0.001) ([Table 2],[Table 3],[Table 4]).

Table 1 Comparison between patients and controls regarding the serum level of growth differentiation factor 15 and hepcidin

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Table 2 Comparison between both autologous and allogenic groups of patients regarding growth differentiation factor 15

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Table 3 Comparison between both autologous and allogenic groups of patients regarding hepcidin

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Table 4 Comparison between both autologous and allogenic groups of patients regarding ferritin

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In both allogenic and autologous groups of patients, there was a statistically significant correlation among GDF15, hepcidin, and ferritin (P<0.001) ([Table 5],[Table 6] and [Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6]).

Table 5 Correlation between growth differentiation factor 15, hepcidin, and ferritin levels in allogenic transplanted patients

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Table 6 Correlation between growth differentiation factor 15, hepcidin, and ferritin levels in autologous transplanted patients

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Figure 1 Correlation between GDF15 and ferritin levels in allogenic transplanted patients. GDF15, growth differentiation factor 15.

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Figure 2 Correlation between hepcidin and ferritin levels in allogenic transplanted patients.

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Figure 3 Correlation between GDF15 and hepcidin levels in allogenic transplanted patients. GDF15, growth differentiation factor 15.

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Figure 4 Correlation between GDF15 and ferritin levels in autologous transplanted patients. GDF15, growth differentiation factor 15.

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Figure 5 Correlation between hepcidin and ferritin levels in autologous transplanted patients.

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Figure 6 Correlation between GDF15 and hepcidin levels in autologous transplanted patients. GDF15, growth differentiation factor 15.

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In allogenic transplanted patients, there were positive correlations between ferritin and alanine transferase (ALT) (P=0.002), ferritin and aspartate transferase (AST) (P=0.004), ferritin and LDH (P=0.001), and ferritin and alkaline phosphate (ALP) (P=0.002). Moreover, there were positive correlations between GDF15 and ALT (0.001), GDF15 and AST (0.002), GDF15 and ALP (0.001), GDF15 and LDH (P=0.001), GDF15 and total bilirubin (P=0.047), and GDF15 and direct bilirubin (P=0.034). In addition, there were positive correlations between hepcidin and ALT (0.022), hepcidin and AST (0.044), hepcidin and ALP (0.033), and hepcidin and LDH (0.010). However, there were no correlations when comparing ferritin, GDF15, and hepcidin with other laboratory tests ([Table 7]).

Table 7 Correlation between age, CBC, biochemical results, date of engraftment, and dose of stem cells and ferritin, growth differentiation factor, and hepcidin levels

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In allogenic transplanted patients, there was a statistically nonsignificant comparison between patients with bacterial infections and patients without bacterial infections regarding the mean levels of ferritin, GDF15, and hepcidin (P=0.249, 0.181, and 0.537, respectively) ([Table 8]). Moreover, there was a statistically nonsignificant comparison between patients with viral infections and patients without viral infections regarding the mean levels of ferritin, GDF15, in (P=0.626, 0.798, and 0.382, respectively) ([Table 9]). Only one patient showed fungal infection.

Table 8 Comparison between ferritin, growth differentiation factor 15, and hepcidin levels in allogenic transplanted patient regarding bacterial infections

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Table 9 Comparison between ferritin, growth differentiation factor 15, and hepcidin levels in allogenic transplanted patients regarding viral infections

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There was a statistically significant difference when comparing the mean levels of ferritin and GDF15 in allogenic patients who had acute graft-versus-host disease (GVHD) with those did not have acute GVHD (P=0.004 and 0.002, respectively). However, there were no statistically significant differences when comparing the mean level of hepcidin in allogenic patients who had acute GVHD with those did not have acute GVHD (P=0.110) ([Table 10]).

Table 10 Comparison between ferritin, growth differentiation factor 15, and hepcidin levels in allogenic transplanted patients regarding acute graft-versus-host disease

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Moreover, there were statistically significant differences when comparing the mean levels of ferritin, GDF15, and hepcidin in allogenic patients who had chronic GVHD with those did not have chronic GVHD (P<0.001) ([Table 11]).

Table 11 Comparison between ferritin, growth differentiation factor 15, and hepcidin levels in allogenic transplanted patients regarding chronic graft-versus-host disease

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In autologous transplanted patients, there were positive correlations between ferritin and ALT (P=0.047) and ferritin and AST (P=0.045). Moreover, there were positive correlations between GDF15 and ALT (0.050), and GDF15 and AST (0.045). Moreover, there were positive correlations between hepcidin and ALT (0.048) and hepcidin and AST (0.045). However, there were no correlations when comparing ferritin, GDF15, and hepcidin with other laboratory tests ([Table 12]).

Table 12 Correlation between age, complete blood count, biochemical results, date of engraftment, and dose of stem cells and ferritin, growth differentiation factor, and hepcidin levels in autologous bone marrow transplanted patients

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In autologous transplanted patients, there were statistically nonsignificant comparisons between patients with bacterial infections and patients without bacterial infections regarding the mean level of ferritin, GDF15, and hepcidin (P=0.402, 0.464, and 0.161, respectively) ([Table 13]). In addition, there was a statistically nonsignificant comparison between patients with viral infections and patients without viral infections regarding the mean level of ferritin, GDF15, and hepcidin (P=0.274, 0.254, and 0.510, respectively) ([Table 14]). Only one patient showed fungal infection.

Table 13 Comparison between ferritin, growth differentiation factor 15, and hepcidin levels in autologous transplanted patient regarding bacterial infections

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Table 14 Comparison between ferritin, growth differentiation factor 15, and hepcidin levels in autologous transplanted patients regarding viral infections

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  Discussion 

HSCT is a potentially curative intervention for malignant and nonmalignant hematologic diseases. Before SCT, hematopoiesis in the recipient should be eliminated by conditioning treatments, including high-dose chemotherapy with or without total body irradiation. After SCT, hematopoiesis is restored by donor stem cells. Major changes in hematopoiesis and iron metabolism occur during and after SCT. As erythropoiesis is completely suppressed by conditioning treatments, SCT is an ideal model for investigating the relationship between iron homeostasis and erythropoiesis in clinical settings [7].

GDF15, a transforming growth factor-b bone morphogenetic protein superfamily member, is a 40-kDa secretory propeptide that is cleaved in the endoplasmic reticulum to release a 25-kDa circulating protein. Under physiological conditions, GDF15 is abundantly expressed only in placenta and macrophage cells. It is also highly expressed in many types of cancer tissues, including colorectal, gastric, esophageal, oral, pancreatic, and others. GDF15 is involved in the inhibition of cell growth, induction of apoptosis, and enhancement of cancer invasiveness in different cancer cell lines [8].

Hepcidin, first identified in human blood and urine as an antimicrobial small peptide, is now considered to be a central molecule that regulates iron metabolism. Hepcidin decreases iron absorption from the intestine and blocks its release from iron stores by downregulating the expression of the cellular iron exporter, ferroprotein. Hepatic expression of hepcidin can be up-regulated by iron loading as well as by inflammatory stimuli such as interleukin-6 [9].

In our study, there is a significant statistical difference when comparing the mean level of GDF15 and hepcidin in patients with autologous and allogenic bone marrow transplantation with the control group (P<0.001).This goes with what Jaspers et al. [10] noticed that there was a statistical significance between hepcidin after transplantation in control and autologous group (P<0.001). Kanda et al. [7] reported also that serum hepcidin level at 1 week before SCT was higher than that in the control sera of healthy volunteers, and it further increased after the day of SCT.

In our study, there were a statistically significant difference between both autologous and allogenic group of patients regarding the mean level of ferritin, GDF15, and hepcidin (P<0.001). These results were in concordance with Jaspers et al. [10], who noticed that allogeneic transplantation compared with autologous transplantation was a major risk factor for IO. Moreover, Atilla et al. [11] said that the incidence of IO in auto-HSCT is approximately 34%, less frequent than in allo-HSCT, and the incidence of IO in the allo-setting reaches up to 60%. Sirvent et al. [12] reported that elevated serum ferritin level was more than 40% in children receiving allogenic transplantation, with a follow-up of more than 10 years. Majhail et al. [13] found elevated serum ferritin in 34% patients after a follow-up of more than 2 years since transplantation. Similarly, Rose et al. [14] reported a ferritin value above normal range in 58% of allogenic transplanted patients after more than 8 years of follow-up.

Regarding patients with allogenic bone marrow transplantation

In our study, we noticed that there was a statistically significant positive correlation between ferritin level and GDF15 level (P<0.001), ferritin level and hepcidin level (P<0.001), and GDF15 level and hepcidin level (P<0.001). This goes with Sakamoto et al. [15] who compared the significance of pretransplant serum ferritin and hepcidin levels on the outcome of allo-HSCT and stated that pretransplant serum hepcidin levels were positively correlated with levels of serum ferritin (P<0.001). However, Eisfeld et al. [16] noticed that in the pretransplant setting, no statistical correlation was found between serum ferritin values before HCT and serum hepcidin concentrations before or after transplantation.

In our study, there was a statistically significant positive correlation between ferritin level and ALT level (P=0.002) and ferritin level and AST level (P=0.004). Moreover, a statistically significant positive correlation was detected between GDF15 level and ALT level (P=0.001) and AST level (P=0.002). Moreover, a statistically significant positive correlation was detected between hepcidin level and ALT level (P=0.022), AST level (P=0.044), and ALP level (P=0.033). This goes with what was stated by Atilla et al. [11] that after HSCT IO was shown to be associated with liver dysfunction. Moreover, Akı et al. [17] noticed a significant positive correlation between serum ferritin levels and histological grade of iron in the hepatocytes in both inpatients with elevated liver enzymes late after HSCT and early in an autopsy series of HSCT patients dying at 50–100 days after transplantation.

In our study, a statistically significant positive correlation was detected between ferritin level in allogenic transplanted patients and LDH (P=0.001), GDF15 and LDH level (P=0.001), and hepcidin and LDH level (P=0.010). This is in concordance with what was stated by Penack et al. [18] that a significant increase of ferritin levels was observed 1–7 days before and at the time of graft rejection (P<0.0001), together with increase in LDH.

In our study, there were no statistically significant differences when comparing between patients with bacterial infections and in patients without bacterial infections regarding ferritin, GDF15, and hepcidin mean levels (P=0.249, 0.181, and 0.537, respectively). Moreover, there were no statistically significant differences when comparing between patients with viral infections and patients without viral infections regarding ferritin, GDF15, and hepcidin mean levels (P=0.626, 0.798, and 0.382, respectively).

However, Kanda et al. [9] stated that when cumulative incidences of documented bacterial and viral infections at day 100 of allogenic transplant were compared according to pretransplant hepcidin levels, the incidence of bacterial, but not viral infection, was significantly higher in the high-hepcidin group than in the low-hepcidin group (P<0.001). Moreover, Akı et al. [17] had not found a similar association with documented infections. Penack et al. [18] noticed that excess mortality in the high-ferritin group was owing to both higher relapse incidence (P=0.007) and increased nonrelapse mortality (P=0.002). Nonrelapse mortality was driven by significantly higher infection-related mortality in the high-ferritin group.

In our study, comparison between patients who had acute GVHD with those did not have acute GVHD regarding ferritin and GDF15 mean level showed that they were higher in patients with acute GVHD, with a statistically significant difference (P=0.004 and 0.002, respectively), but there was a statistically nonsignificant difference regarding hepcidin (P=0.110). Moreover, comparison of ferritin, GDF15, and hepcidin mean level in allogenic patients who had chronic GVHD with those who did not have chronic GVHD showed that it was higher in patients with chronic GVHD, with a statistically significant difference in-between (P<0.001). This goes with what was reported by Pullarkat et al. [19], who evaluated the effect of pretransplant ferritin levels on acute GVHD in a prospective cohort study of 190 allo-HSCT patients and noticed that acute GVHD was more common in patients with high-ferritin levels (>1000 ng/ml). However, Mahindra et al. [20] demonstrated the decreased incidence of chronic GVHD associated with pretransplant ferritin levels of more than 1910 µg/l in 222 patients.

Moreover, Maradei et al. [21] reported that there was no relation detected between serum ferritin levels and acute/chronic GVHD. Wahlin et al. [22] noticed elevated pretransplant ferritin levels of more than 400 µg/l were associated with a lower risk of chronic GVHD (P=0.003) in 309 allo-HSCT recipients. They hypothesized that ferritin might show an immunosuppressive effect and thus reduce the incidence of GVHD following HSCT. Eisfeld et al. [16] stated that there was no association between the occurrence and the severity of GVHD on one side and pre-HCT or post-HCT body hepcidin levels on the other side. Penack et al. [18] stated that ferritin increased significantly at the time of VOD (P=0.0067), at the time of intestinal (P<0.0001) and skin GVHD (P<0.0001), and bacteremia (P=0.0029).

Sirvent et al. [12] stated that significant GvHD (P=0.034) was significantly correlated with a higher prevalence of IO. Chakrabartty et al. [23] found no effect of hepcidin on the occurrence/severity of GVHD (P=0.64) or the incidence of relapse. In addition, Yan et al. [24] reported that high pre-transplantation serum ferritin was closely associated with a lower incidence of chronic GVHD (P<0.05), and also they noticed no significant relationship between elevated pre-transplantation serum ferritin and acute GVHD (P=0.70). Penack et al. [18] also noticed that acute and chronic GVHD incidence or severity was not associated with serum ferritin levels.

Regarding patients with autologous bone marrow transplantation

In our study, a statistically significant positive correlation was detected between ferritin level and GDF15 level (P<0.001), ferritin level and hepcidin level (P<0.001), and GDF15 level and hepcidin level (P<0.001). This goes with what Jaspers et al. [10] reported that hepcidin level increased from day 60 after autologous transplantation onwards, in parallel to the increase in ferritin.

Maradei et al. [21] confirmed the association between high-ferritin serum levels before transplantation and the occurrence of sinusoidal obstruction syndrome, in a large cohort of both autologous and allogeneic HSCT recipients. In our study, we observed a statistically significant positive correlation between ferritin level in autologous transplanted patients and ALT, with P value of 0.047, and AST, with P value of 0.045. Moreover, a statistically significant positive correlation was detected between GDF15 level in autologous transplanted patients and ALT, with P value of 0.050, and AST, with P value of 0.045. In addition, a statistically significant positive correlation was detected between hepcidin level in autologous transplanted patients and ALT, with P value of 0.048, and AST, with P value of 0.045. McKay and colleagues studied 76 survivors of allogeneic and autologous bone marrow transplantation who were at least 1 year after transplant and found that the majority (88%) had raised ferritins. Impaired liver function was common in these patients, suggesting that IO may be an important contributing factor to liver disease in the stable posttransplant setting. This view is supported by the observation of improving liver function tests in ten patients after a trial of venesection therapy [24].

Miceli and colleagues observed that IO, assessed by bone marrow biopsy, was an independent risk factor for severe infection among patients with multiple myeloma receiving autologous HSCT [25]. However, this was against our observations, where comparison between ferritin, GDF15, and hepcidin levels in autologous patients with bacterial infections and in patients without bacterial infections was statistically nonsignificant (P=0.402, 0.464, and 0.161, respectively). Moreover, comparison between ferritin, GDF15, and hepcidin levels in autologous patients with viral infections and in patients without viral infections was statistically nonsignificant (P=0.274, 0.254, and 0.510, respectively).

In both allogenic and autologous transplanted patients in our study, a statistically nonsignificant correlation was detected between ferritin level, GDF15 level, and hepcidin level with dose of stem cells, engraftment date, age of patients, white blood cell, hemoglobin, platelet, bilirubin level, international normalization ratio, and electrolytes of the patients.

Conclusion and recommendations

These findings promote the previous suggestions about the role of both GDF15 and hepcidin in IO and liver dysfunction in patients with acute and chronic GVHD after transplantation, indicating that they are important targets for further investigations, and raise the possibility for using both biomarkers as an indicator of posttransplantation complications.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14]