scholarly journals Dysregulated Neutrophil Iron Homeostasis in β-Thalassemia Impairs Phagocytosis and Reactive Oxygen Species Production

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 942-942
Author(s):  
Sreenithi Santhakumar ◽  
Devi V.J ◽  
Leo stephen.R ◽  
Aruna Barade ◽  
Uday Prakash Kulkarni ◽  
...  
Keyword(s):  
Iron Overload ◽  
Oxidative Burst ◽  
Iron Homeostasis ◽  
Transferrin Saturation ◽  
Thalassemia Major ◽  
Negative Association ◽  
Beta Thalassemia ◽  
Oxygen Species ◽  
Soluble Transferrin Receptor ◽  
Healthy Donors

Abstract Introduction Beta thalassemia is an inherited disorder characterised by ineffective erythropoiesis leading to anemia and secondary iron overload. Neutrophils are the first line of innate immune defence against infection is dysfunctional in thalassemia patients. Iron is required for the oxidative response of neutrophils to allow the production of reactive oxygen species (ROS). However, the role of iron contributing to the neutrophil dysfunction is unclear. This is the first study to characterise the neutrophil iron metabolism in β-thalassemia and its association with oxidative burst capacity, phagocytosis, and systemic iron homeostasis. Method Sixteen thalassemia patients and fourteen healthy individuals were recruited in the department of Haematology, Christian Medical College, Vellore, India. Neutrophils were purified from human whole blood collected in EDTA tube, using neutrophil magnetic isolation kit (Miltenyi Biotec). Purified population (>95%) was confirmed by the presence of the surface marker CD62L evaluated using flow cytometry. Haematological parameters were analysed according to standard methods. Serum ferritin, iron, soluble transferrin receptor were measured using immunoassay. Serum hepcidin was measured using ELISA. Neutrophil RNA was isolated using trizol method and was reverse transcribed into complementary DNA using QIAGEN kit. The relative quantification of iron related genes were measured using real-time PCR. In oxidative burst assay, neutrophils were incubated with dihydrorhodamine 123 (DHR) and stimulated with Phorbol 12-Myristate 13-Acetate (PMA). Respiratory burst of the cell was analysed by flow cytometry. Phagocytosis and acidification capacity of human neutrophils were quantified using the pHrodo Green Staphylococcus aureus BioParticles kit (Thermo Fisher). Acquisition was performed using the Beckman Coulter(Navios) flow cytometer and analysed using kaluza software. Statistical analysis was performed using SPSS software. Results We investigated a cohort of β thalassemia Major (n=5), intermedia (n=6) and sickle beta thalassemia (n=5) patients who were on regular iron chelation therapy. The demographic and biochemical parameters are tabulated in Table 1. Serum iron, ferritin levels and transferrin saturation were significantly increased in thalassemia cohort as compared to healthy donors (Fig1a). There was no significant association between ferritin and hepcidin levels. The percentage of neutrophils in thalassemia was significantly reduced incomparision to healthy donors (p=0.032). Oxidative burst capacity of neutrophils from thalassemia major and intermedia patients were significantly decreased (p=0.002) compared to healthy donors upon stimulation with PMA (Fig1b). Neutrophil phagocytosis capacity indicated by the relative amounts of phagocytized fluorescein S.aureus particles were significantly lower in thalassemia patients compared with controls, after 15min/30min incubation (Fig1c). The recognition capacity of neutrophils towards bioparticles significantly decreased at 45-minute incubation in patients (p=0.017) (Fig1d). Serum iron overload and transferrin saturation had negative association with neutrophil phagocytosis capacity (r=-0.714; p=0.045 & r=-0.857; p=0.014), respectively. Neutrophil iron related gene expression was analysed and found significantly lower expression of FPN 1A (FPN1 containing iron regulatory element (IRE)), DMT1B without IRE region and IRP2 respectively (p=0.029, p=0.029 & p=0.016) (Fig1e). FPN1B without IRE region was upregulated in thalassemia patients (p=0.016). Serum ferritin had positive correlation with FPN1B (r=0.786; p=0.036). Soluble transferrin receptor had negative association with DMT1A (containing IRE region) and IRP2 respectively (r=-0.900; p=0.037 and r=-0.750; p=0.052). Aberrant neutrophil function was found in all thalassemia patients. Although oxidative burst activity was decreased in thalassemia major and intermedia patients, sickle β-thalassemia patients had normal burst activity. Systemic iron status had inverse correlation with phagocytosis capacity of neutrophils. Dysregulation of iron transporters in neutrophils was indicated by decreased expression of DMT1 and augmented FPN1B expression, despite systemic iron overload. These findings have to be explored in a larger cohort to elucidate the clinical significance. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Liver Enzymes in Children with beta-Thalassemia Major: Correlation with Iron Overload and Viral Hepatitis

2015 ◽  
Vol 3 (2) ◽  
pp. 287-292 ◽  
Author(s):  
Khaled M. Salama ◽  
Ola M. Ibrahim ◽  
Ahmed M. Kaddah ◽  
Samia Boseila ◽  
Leila Abu Ismail ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Iron Overload ◽  
Viral Hepatitis ◽  
Serum Ferritin ◽  
Liver Enzymes ◽  
Transferrin Saturation ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Elevated Liver Enzymes ◽  
Hcv Antibody

BACKGROUND: Beta Thalassemia is the most common chronic hemolytic anemia in Egypt (85.1%) with an estimated carrier rate of 9-10.2%. Injury to the liver, whether acute or chronic, eventually results in an increase in serum concentrations of Alanine transaminase (ALT) and Aspartate transaminase (AST).AIM: Evaluating the potentiating effect of iron overload & viral hepatitis infection on the liver enzymes.PATIENTS AND METHODS: Eighty (80) thalassemia major patients were studied with respect to liver enzymes, ferritin, transferrin saturation, HBsAg, anti-HCV antibody and HCV-PCR for anti-HCV positive patients.RESULTS: Fifty % of the patients were anti-HCV positive and 55% of them were HCV-PCR positive. Patients with elevated ALT and AST levels had significantly higher mean serum ferritin than those with normal levels. Anti-HCV positive patients had higher mean serum ferritin, serum ALT, AST and GGT levels and higher age and duration of blood transfusion than the negative group. HCV-PCR positive patients had higher mean serum ferritin and serum ALT and also higher age and duration of blood transfusion than the negative group.CONCLUSION: Iron overload is a main leading cause of elevated liver enzymes, and presence of HCV infection is significantly related to the increased iron overload.

International Comparison Study of Toxic Iron Assays in Patients with Iron Overload Disorders

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4033-4033
Author(s):  
Louise De Swart ◽  
Jan C.M. Hendriks ◽  
Lisa Van der Vorm ◽  
Ioav Z. Cabantchik ◽  
Patricia J. Evans ◽  
...  
Keyword(s):  
Iron Overload ◽  
Research Funding ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
The Other ◽  
Serum Samples ◽  
Excess Iron

Abstract Background: Imbalances in iron homeostasis result in a variety of disorders. Excess iron accumulates in the circulation and tissues of patients with hereditary hemochromatosis (HH), iron-loading anemia (β-thalassemia major and intermedia (Thal), myelodysplastic syndromes (MDS) and sickle cell disease after transfusion (SCD). To prevent iron-induced tissue damage, detection of impending iron toxicity is needed before complications develop and become irreversible. Plasma non-transferrin bound iron (NTBI) and its labile (redox active) component (LPI) are thought to be potentially toxic forms of iron identified in the serum of patients with iron overload. Objective: To increase our insights into NTBI and LPI concentrations measured by the current worldwide leading analytical assays in four different categories of iron overloaded patients (HH, Thal, MDS, transfused SCD) undergoing various treatments (phlebotomies, iron chelation, red blood cell transfusions). Methods: We compared 10 different assays (5 NTBI, 1 NTBI isoform specific and 4 LPI) as part of an international inter-laboratory study. Serum samples were from 60 patients with 4 iron overload disorders. Serum samples were split into two aliquots, coded (blinded), stored at -80°C and shipped for analysis to 5 different laboratories worldwide. Laboratories performed duplicate measurements on each aliquot of a serum sample on 2 different days, resulting in a total of 4 measurements for each sample. Some laboratories provided multiple assays. Results: NTBI and LPI measurements in the serum of iron-overloaded patients showed good reproducibility with a high between-sample (range 67.1-97.2%) and a low within-sample variance (0-2.2%) relative to the total variance of each assay. Absolute NTBI and LPI levels differed considerably between assays. Four assays (2 LPI and 2 NTBI) also reported negative values. LPI levels were ± 10% of the NTBI levels. Highest levels were observed in patients with naive HH and naive Thal intermedia, transfusion-dependent MDS and transfusion-dependent Thal major. These 4 patients groups also had the highest transferrin saturation (TSAT) levels, but only 3 of them were among the groups with the highest ferritin levels. Eight (4 LPI and 4 NTBI) of the 10 assays could discriminate well between iron overload diseases. In general correlations were highest within the same group of NTBI or LPI assays. Interestingly, one of the LPI assays showed better correlations with NTBI assays (range rs=0.85-0.90) than with the other LPI assays (range rs=0.61-0.77). In contrast, one of the NTBI assays showed better correlations with LPI assays (range rs=0.67-0.75) than with the other NTBI assays (range rs=0.50-0.59). The assays show a hyperbolic relation with TSAT; NTBI and LPI concentrations only substantially increase above a certain TSAT level of ~70% and ~ 90%, respectively. This is illustrated for both a representative NTBI (Figure 1A) and LPI assay (Figure 1B). This relation does not exist between any of the assays and ferritin (Figure 1C,D). Conclusions: While NTBI and LPI values of various assays are well correlated and discriminate between iron overload disorders, absolute values differed considerably between assays. Both standardization of assays and clinical outcome studies to determine clinically relevant toxic thresholds are needed. At present TSAT may provide a useful alternative in the clinical management of patients with iron overload. Figure 1: Relation between representative assays and TSAT, Ferritin. Assay results are given for day 2 as duplicate measurements (circle and square). Figure 1:. Relation between representative assays and TSAT, Ferritin. Assay results are given for day 2 as duplicate measurements (circle and square). Disclosures De Swart: Novartis Europe: Research Funding. Swinkels:Novartis Europe: Research Funding.

scholarly journals The Dysregulation of Hepcidin-Ferroportin Axis in Childhood Acute Lymphoblastic Leukemia Survivors after Completion of Chemotherapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Hsi-Che Liu ◽  
Ting-Chi Yeh ◽  
Jen-Yin Hou ◽  
Ting-Huan Huang ◽  
Chia-Yu Sung ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Iron Overload ◽  
Lymphoblastic Leukemia ◽  
Transferrin Saturation ◽  
Thalassemia Major ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Beta Thalassemia ◽  
Childhood All ◽  
Beta Thalassemia Major

Background The hepcidin-ferroportin axis is known to play the essential role on iron homeostasis in human. The binding of hepcidin to ferroportin (FPN) on the membranes of iron-exporting cells induces the ubiquitination of FPN and thereby decreases the delivery of iron to plasma. Low hepcidin with high FPN was well established in patients with ineffective erythropoiesis, e.g. beta-thalassemia major and myelodysplastic syndrome. On the other hand, studies showed increased hepcidin accompanied with decreased FPN in patients with some cancers. Further, anemia in multiple myeloma and Hodgkin's lymphoma were reported to be associated with high hepcidin levels (Blood 2008;112:4292). Here, we investigated the function of the hepcidin-ferroportin axis in childhood acute lymphoblastic leukemia (ALL) survivors who completed chemotherapy. Methods Thirty-three children, aged ≤18 years with ALL and completing TPOG-ALL-2013 protocol before June 30, 2020, were enrolled (ALL-off Gr). According to the treatment protocol, they had been classified as standard-risk (SR) in 20, high-risk (HR) in 12 and very-high-risk (VHR) in 1, respectively. Thirty-eight healthy siblings were assigned as the normal controls (normal Gr) after exclusion of acute illness and iron deficiency. Twenty newly-diagnosed ALL children (ALL-Dx Gr) who did not have sepsis at diagnosis (Dx), and 13 patients with beta-thalassemia major (TM Gr) who received regular transfusion were also enrolled. Serum iron, total iron-binding capacity, ferritin, hepcidin and FPN were collected at Dx in ALL-Dx Gr and at 6-month follow-up after completion of chemotherapy in ALL-off Gr. Selected biochemical assays were checked in normal Gr and TM Gr on the day of routine RBC transfusion. Hepcidin and FPN levels of peripheral blood were measured using ELISA kits (DRG, EIA-5782 for hepcidin & Elabscience, E-EL-H2355 for FPN, respectively). Results The clinical features and biochemical data of all patients are shown in Table 1. The hepcidin and FPN of normal Gr were comparable with those of reference papers. The low hepcidin, high FPN and relatively low hepcidin/ferritin of TM Gr were in consistent with those of published reports. There were no significant differences of age (P =.243) and gender (P =.899) between ALL-off Gr and normal Gr. The ferritin and transferrin saturation between ALL-Dx and ALL-off Grs showed statistical difference (P <.001 and P =.02, respectively). In figure 1, the hepcidin and FPN levels of ALL-Dx Gr were significantly higher than those of the normal Gr (P <.001). The trends remained but did not reach statistical significances between ALL-off and normal Grs. None of ALL-off Gr had mutation of HFE C282Y/H63D, HJV C119F or SLC40A1 C326S. Further, in ALL-off Gr, 6 patients had abnormal ferritin levels (>300 ng/mL; median, 871.55; range, 351.6-959.0)(high-ferritin). MRI scans of liver and heart from the 6 high-ferritin patients did not show any evidence of iron overload. In Figure 2, hepcidin levels were significantly higher in ALL-off patients with high-ferritin or receiving cumulative RBC transfusions >10 units. And ALL-off patients with high-ferritin, RBC transfusions >10 units or receiving HR/VHR treatment regimens had significantly higher FPN levels. Multivariate analysis demonstrated only high-ferritin predicted significantly higher hepcidin (P =.02) and FPN (P <.001) levels in ALL-off Gr. Conclusions The dysregulation of hepcidin-ferroportin axis showed high hepcidin and uncontrolled FPN hyperactivity at Dx of childhood ALL which may point to the impaired down-regulation of FPN by hepcidin. Our findings imply the impaired mechanism may not be fully recovered in ALL survivors after completing chemotherapy, especially those with ferritin >300 ng/mL, HR/VHR groups or receiving higher RBC transfusions. The routine monitoring of the axis function could facilitates the early detection of iron overload in liver and heart. Disclosures No relevant conflicts of interest to declare.

scholarly journals Early detection of premature atherosclerosis in β-thalassemia patients by measuring carotid intima-media thickness

QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
W E Ibrahim ◽  
O I Youssef ◽  
H G A Ali ◽  
D M A Alnagar
Keyword(s):  
Carotid Artery ◽  
Early Detection ◽  
Iron Overload ◽  
Lipid Profile ◽  
Intima Media Thickness ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Thalassemia Intermedia ◽  
Premature Atherosclerosis ◽  
Media Thickness

Abstract Background Beta-thalassemia patients still suffer from many complications. Transfused patients may develop complications related to iron overload including growth retardation and failure or delay of sexual maturation, cardiac involvement (dilated cardiomyopathy or rarely arrhythmia), liver (fibrosis and cirrhosis), endocrine glands (diabetes mellitus, hypogonadism, insufficiency of parathyroid, thyroid, pituitary and less commonly, adrenal glands). Purpose The present study was undertaken to evaluate the role of Carotid artery intima media thickness (CIMT) measurement as an early detector of premature atherosclerosis in beta-thalassemia children and early adolescents and its relation to biochemical risk factors as iron overload and lipid profile. Patients and Method Twenty-two β-thalassemia major (TM), 8 β-thalassemia intermedia (TI) with confirmed diagnosis of beta-thalassemia (major and intermedia) proved by clinical and laboratory investigations, frequent blood transfusion, chelation therapy with their age ranging from 10 to18 years old and 30 age-and sex matched healthy controls were included. Lipid profile (by colorimetric assay), serum ferritin, and CIMT measurements using high-resolution B-mode ultrasonography were estimated. Results CIMT of thalassemic patients (major and intermedia) was highly significantly increased compared to controls with no significant difference between β-thalassemia major and β thalassemia intermedia groups could be detected. CIMT was positively correlated with serum ferritin, TG, Total cholesterol level in both diseased groups and LDL level in B-TM group only. This provides a good evidence of the presence of premature atherosclerosis in vascular-free TM and TI patients and its relation to increased body iron and dyslipidemia. Conclusion Carotid artery intima media thickness represented a simple, accurate and non-invasive method for early detection of premature atherosclerosis which started early in β- thalassemia patients This study identified a relationship between body iron status, dyslipidemia and increased carotid IMT..

Does Gene Therapy in Beta Thalassemia Normalize Novel Markers of Ineffective Erythropoiesis and Iron Homeostasis?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 816-816 ◽  
Author(s):  
Alexis A. Thompson ◽  
Tomas Ganz ◽  
Mary Therese Forsyth ◽  
Elizabeta Nemeth ◽  
Sherif M. Badawy
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Research Funding ◽  
Iron Homeostasis ◽  
Beta Thalassemia ◽  
Ineffective Erythropoiesis ◽  
Liver Iron ◽  
Equity Ownership

BACKGROUND: Ineffective erythropoiesis in thalassemia alters iron homeostasis, predisposing to systemic iron overload. Successful allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia major corrects anemia, should eliminate ineffective erythropoiesis (IE) and normalize iron homeostasis (IH). Whether gene therapy (GT) will fully correct IE and IH is not known. This cross-sectional observational study evaluated the iron status of patients with beta thalassemia following HSCT or GT, and compared them with cohorts of patients with thalassemia intermedia (TI) or transfusion-dependent thalassemia (TDT) using recently introduced biomarkers along with imaging studies and other clinical assessments to better understand and characterize IE and IH across groups. METHODS: We evaluated a convenience sample of 29 participants with beta thalassemia (median age 25 years, IQR 21-35; females 55%; Asian 52%). Participants in the HSCT (n=6) and GT (n=10) groups were evaluated on average 116.5 and 46.9 months following cell infusion, respectively. TDT patients (n= 9) were evaluated pre-transfusion and off iron chelation for at least 7 days, and TI (n=4) were un-transfused or not transfused in >3 years. Clinical lab assessments and MRI R2*/ T2* to assess heart and liver iron burden including post-processing, were performed using local clinical protocols. ELISAs for hepcidin, erythroferrone (Erfe) and GDF-15 were performed in a blinded manner. RESULTS: Median values for all IE and IH parameters tested were normal in the HSCT group, and were significantly lower than in all other groups. There were significant differences among all groups for hemoglobin (p=0.003), erythropoietin (Epo) (p=0.03), serum ferritin (SF) (p=0.01), transferrin (p=0.006), soluble transferrin receptor (sTfR) (p=0.02), serum hepcidin: serum ferritin (H:F) ratio (p=0.006), Erfe (p=0.001), GDF15 (p=0.003), and liver iron content (LIC) by MRI R2* (p=0.02). H:F ratio, a surrogate for predisposition to systemic iron loading, inversely correlated with Erfe (rs= -0.85, p<0.0001), GDF15 (rs= -0.69, p=0.0001) and liver R2* (rs= -0.66, p=0.0004). In a multivariate analysis, adjusted for gender and race, H:F ratio and Epo levels predicted Erfe and GDF15 (p=0.05 and p=0.06; p=0.01 and p=0.05), respectively. Even after excluding GT patients that are not transfusion independent (N=2), SF, Epo, sTfR and hepcidin remain abnormal in the GT group, and there were no significant differences in these parameters between GT and TDT. However, novel biomarkers of IH and IE suggested lower ineffective erythropoiesis in GT compared to TDT (median (IQR) Erfe, 12 (11.6-25.2) vs. 39.6 (24.5-54.7), p=0.03; GDF15, 1909.9 (1389-4431) vs. 8906 (4421-12331), p=0.02), respectively. Erfe and GDF15 were also lower in GT compared to TI, however these differences did not reach statistical significance. There were no differences in hepcidin, ferritin, or H:F by race, however Erfe and GDF15 were significantly lower in Asians compared to non-Asians (p=0.006 and p=0.02, respectively). CONCLUSION: Nearly 4 years post infusion, most subjects with TDT treated with GT are transfusion independent with near normal hemoglobin, however, studies in this limited cohort using conventional measures suggest IE and IH improve, particularly when transfusion support is no longer needed, however they remain abnormal compared to HSCT recipients, who using these parameters appear to be cured. STfR did not detect differences, however GDF15 and Erfe were more sensitive assays that could demonstrate significant improvement in IE and IH with GT compared to TDT. Contribution to IE by uncorrected stem cell populations post GT cannot be determined. Transduction enhancement and other recent improvements to GT may yield different results. Longitudinal studies are needed to determine if thalassemia patients treated with GT will have ongoing IE predisposing to systemic iron overload. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership. Nemeth:Intrinsic LifeSciences: Consultancy, Equity Ownership; Silarus Therapeutics: Consultancy, Equity Ownership; Keryx: Consultancy; Ionis Pharmaceuticals: Consultancy; La Jolla Pharma: Consultancy; Protagonist: Consultancy.

Down Regulation of Hepcidin and Interleukin 1-Alpha in Pbmc from Patients with Beta thalassemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2880-2880
Author(s):  
Maria-Eliana Lai ◽  
Stefania Vacquer ◽  
Maria Paola Carta ◽  
Claudia Mulas ◽  
Pierluigi Cocco ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Homeostasis ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Diagnostic Tools ◽  
Beta Thalassemia ◽  
Blood Transfusions ◽  
Mrna Levels ◽  
Down Regulation ◽  
Hepcidin Mrna

Abstract Thalassemia is an inherited blood disease characterized by low levels or absence of normal globin chains. Severe forms of thalassemia, thalassemia major (TM), require regular blood transfusions, the main cause of secondary hemosyderosis. However, iron overload is a potential complication, even in patients (pts) with thalassemia intermedia (TI), who do not require transfusions. Among them, iron overload is mainly the result of an excessive absorption of dietary iron, caused by a down-regulation of hepcidin, an hepatic hormone that acts as a major regulator of systemic iron homeostasis. Very low mRNA levels of hepcidin have been reported in urine as well as in liver biopsies from patients with TI. It has been also reported that, interleukin-1 alpha (IL-1α) stimulates hepcidin transcription, raising the question as to whether a down-regulation of this cytokine may be responsible, at least partially, for the excessive iron absorption occurring in patients with TI. Here, we assessed whether IL-1α was involved in hepcidin regulation in β-thalassemia. Peripheral blood mononuclear cells (PBMCs) were isolated from 6 TM pts, 8 TI pts and 6 controls. mRNA was obtained from PBMCs by RT-PCR. Hepcidin mRNA levels were reduced in both TM and TI pts when compared to the age matched normal controls. Neverthless, hepcidin mRNA levels were significantly lower in TI pts, as compared to TM pts receiving regular blood transfusions. Among TI pts lower hepcidin mRNA level was associated with lower level of IL-α. Tumor necrosis factor alpha (TNF-α) does not seem to be involved in the regulation of hepcidin transcription. Interestingly, the levels of mRNA expression of acyl-CoA-cholesterol acyltransferase (ACAT), the enzyme responsible for intracellular cholesterol ester accumulation, and thus, for atherosclerotic plaque formation were strongly induced in PBMCs in TI pts. These results suggest that PBMCs hepcidin and IL-1-α measurements could possibly be used in the future as simple, ease and sensible diagnostic tools for the detection of iron overload in patients with thalassemia. ACAT expression may even be used as therapeutic target in preventing atherosclerotic complications such as pulmonary thromboembolism, cerebral thrombosis, and leg ulcers. frequently occurring in such patients.

Growth Differentiation Factor 15 (GDF15) and Erythropoietin (EPO) Levels in Beta Talassemia Major Patients.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1881-1881
Author(s):  
Ilaria Salussoglia ◽  
Gisella Volpe ◽  
Silvia Fracchia ◽  
Simona Roggero ◽  
Filomena Longo ◽  
...  
Keyword(s):  
Iron Status ◽  
Clinical Status ◽  
Transferrin Saturation ◽  
Iron Chelation ◽  
Serum Levels ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Transfusion Therapy ◽  
Beta Thalassemia Major ◽  
The Mean

Abstract Background: The serum level of GDF15 has been recently indicated as a possible marker of erythropoiesis (Tanno et al., Nature 2007) suggesting a role of its over-expression in contributing to iron overload in thalassemia syndromes by inhibiting hepcidin expression. The aim of present study has been to evaluate GDF15 serum levels in a homogeneous series of thalassemia patients and the relationship with transfusional parameters and iron status markers. Methods: A group of consecutive patients with beta thalassemia major followed at our institution were included in the study. All patients were on regular transfusion and iron chelation treatment. Quantification of GDF15 on serum samples was performed with DuoSet ELISA for human GDF15 (R&D Systems) following the manufacturer’s protocol (Tanno et al., Nature 2007). Each patient had also a blood test for haemoglobin (Hb), serum iron, ferritin, transferrin, transferrin saturation and EPO levels. Liver Iron Concentration by SQUID and cardiac iron by MRI T2* have been assessed. The mean hemoglobin levels of the previous year (pre-transfusional, post-transfusional and mean) have been calculated for each individual. The presence of mild thalassemic mutations was used to classify mild or severe genotype. Clinical status has been assessed on the presence/absence of main complications (heart disease, liver disease, diabetes, hypothyroidism). Statistical analysis was performed using the software Statistica (StatSoft). Results: One hundred-forty patients (73 male, 67 females) were studied. The mean age was 27.9 ± 9.0 years (range: 3.5–42). One hundred (71%) were splenectomised. Betathalassemia major patients had elevated GDF15 serum levels (mean 6892 ± 6894 pg/mL; range 720–52521) in comparison with healthy volunteers (273 ± 104 pg/mL; range 129–401). GDF 15 levels were strongly related to EPO levels (r=0,81; p<0,001). GDF15 levels were not related with age, gender, spleen, clinical status and iron markers. Patients with a severe genotype had higher GDF15 levels than mild genotype patients. GDF15 levels had a negative correlation with Hbs (p<0,05 for actual Hb and pre-transfusional Hb; p<0,001 for post-transfusional Hb and mean Hb). In thalassemia major patients with a severe genotype, GDF15 levels within thrice the normal range have been observed only in patients with pre-transfusional Hb above 9,6, post-transfusional Hb above 12,5 and a mean Hb above 11,3. Conclusions: In beta thalassemia major patients on regular transfusion and iron chelation, serum GDF15 levels are high, inversely related to the haemoglobin levels maintained. Further studies of this marker may lead to a rethinking of the optimal transfusion therapy in these conditions.

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