scholarly journals Disbalanced Erythroid Ferroportin Expression Contributes to Ineffective Erythroid Output in Anemia of Chronic Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3533-3533
Author(s):  
Verena Petzer ◽  
Piotr Tymoszuk ◽  
Markus Seifert ◽  
Natascha Brigo ◽  
Philipp Grubwieser ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Splenic Tissue ◽  
Intracellular Iron ◽  
Anemia Of Chronic Disease ◽  
Erythroid Precursor ◽  
Protein Levels ◽  
Tissue Iron ◽  
Bone Marrow Iron ◽  
Erythroid Development

Iron is essential for proper red blood cell development. During erythroid maturation in the bone marrow iron dependency starts at the basophilic stage, and lasts until the reticulocyte stage. Thereby the majority of iron is delivered in a Tf-TfR dependent manner and is incorporated in hemoglobin of developing red cells. Just recently, it has been discovered that erythroblasts and mature red blood cells not only incorporate iron but also express the sole known iron exporter, ferroportin (Fpn), throughout their development, and thus can also effectively export iron that is not used for heme synthesis. Fpn surface expression is regulated via hepcidin, a hepatocyte-derived peptide, which binds directly to surface-Fpn, inducing its internalization and consequent degradation in lysosomes. Among patients suffering from anemia of chronic disease (ACD), hepcidin is constantly induced due to long-lasting inflammation, leading to impaired iron export capacity. While splenic tissue iron overload, which is associated with the restricted capacity of red pulp macrophages to export recycled iron form degraded erythrocytes is well established, the effect of high hepcidin levels in ACD and its consequences on developing erythroblasts in the bone marrow has not been investigated. First we induced chronic kidney disease (CKD) in C57BL/6 mice via an Adenine - diet. Alongside microcytic anemia, reduced Tf-saturation, increased hepcidin levels and splenic tissue iron overload, we found a ~38% increase in tissue iron content in bone marrows of CKD mice compared to control mice. In parallel, Western blot analysis revealed massively reduced Fpn protein levels in the bone marrow. Moreover, the individual iron-dependent erythroblast precursor populations (i.e. basophilic, polychromatic, orthochromatic erythroblasts and reticulocytes) showed higher levels of intracellular iron as measured by Calcein fluorescence via flow cytometry. We could further corroborate these results by Western blot analysis and flow cytometric work-up of reticulocytes and mature red blood cells in the blood stream, both revealing highly reduced Fpn protein levels on these cells in mice suffering from CKD. Based on these findings we performed additional experiments to investigate the detrimental effect of iron overload on erythroid development and to exclude the possibility of a direct inflammation-regulated process in the CKD model. Therefor we established an iron-overload mouse model via repeated parenteral iron dextran applications. Despite significantly increased Tf-saturation levels as well as hepatic hepcidin levels (>4-fold) and reduced bone marrow Fpn protein levels among iron-treated mice, iron overload led to higher stress levels among erythroid precursor populations. In detail, we could demonstrate via flow cytometry that higher intracellular iron pools (measured by Calcein), correlated with higher levels of mitochondrial stress and higher levels of lipid peroxidation (determined by mean fluorescence intensity of MitoSOX and Bodipy 581/59, respectively). These data indicate that iron is a critical regulator of stress during erythroid development and can be regulated via the hepcidin-Fpn axis. In conclusion, we clearly show that Fpn expression on erythroid precursor cells is inversely regulated to systemic hepcidin levels and affects the erythropoietic bone marrow iron content. Moreover our results reveal a novel model for ineffective erythroid output in patients suffering from ACD due to hepcidin-triggered Fpn internalistation. Based on our data, anti-hepcidin treatment strategies are promising to overcome restricted erythropoiesis, which will be evaluated in future experiments. Disclosures Theurl: Kymab Ltd: Consultancy, Equity Ownership.

Down-Regulation of TfR1 Increases Erythroid Precursor Enucleation and Hepatocyte Hepcidin Expression in ß-Thalassemic Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 754-754
Author(s):  
Huihui Li ◽  
Tenzin Choesang ◽  
Weili Bao ◽  
Lionel Blanc ◽  
Huiyong Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Critical Role ◽  
Nuclear Fraction ◽  
Double Heterozygote ◽  
Ineffective Erythropoiesis ◽  
Liver Iron ◽  
Erythroid Precursor ◽  
Erythroid Precursors ◽  
Serum Hepcidin

Abstract Transferrin-bound iron binding to transferrin receptor 1 (TfR1) is essential for erythropoiesis, and TfR1 is found in highest concentrations on erythroid precursors due to high iron requirement for hemoglobin (Hb) synthesis. Diseases of ineffective erythropoiesis such as β-thalassemia, are characterized by anemia, expanded and extramedullary erythropoiesis, and iron overload. Iron overload results from insufficient hepcidin, a peptide hormone secreted by hepatocytes in response to iron load. In β-thalassemia, hepcidin is relatively suppressed as a consequence of erythroid expansion. Erythroferrone (ERFE), a recently described erythroid-derived hepcidin suppressor, has been proposed as the mechanism and found in higher concentration in bone marrow of β-thalassemic mice. We previous demonstrate that exogenous transferrin (Tf) ameliorates anemia in β-thalassemic mice, reversing splenomegaly, hepcidin suppression, and iron overload and recently confirmed a decrease in Erfe expression in erythroid precursors from Tf-treated β-thalassemic mice. We observed that although Tf-treated β-thalassemic mice exhibit a further decrease in MCV and MCH, suggesting a relatively more iron restricted erythropoiesis, TfR1 expression is decreased. We hypothesize that TfR1 is central to Tf's effect on erythropoiesis in β-thalassemic mice. Last year, we presented our analysis of th3/+ TfR1+/- double heterozygote mice which exhibit reversal of all erythropoiesis- and iron-related pathology in th3/+ mice, confirming our observations in Tf-treated β-thalassemic mice and further supporting our hypothesis. To evaluate the mechanism involved, we observed that despite suppressed TfR1 concentration in reticulocyte (P=0.006) and sorted bone marrow erythroid precursors (P=0.0004) from Tf-treated th1/th1 mice, cell surface TfR1 expression decreased on reticulocytes (P=0.003) but was surprisingly increased on late stage erythroid precursors (P=0.007) (Figure 1A), suggesting that exogenous Tf influences erythroid precursor enucleation. Because we previously demonstrate decreased serum soluble TfR1 in Tf-treated th1/th1 mice [Liu J Blood 2013], we hypothesize that exogenous Tf alters TfR1 shedding from erythroid precursor membranes, promoting enucleation and improved terminal differentiation. We observed decreased enucleation using syto60 in flow cytometry of fetal liver cells (FLC) from th3/+ relative to wild type (WT) embryos (35 vs. 51%, P=0.03) which is normalized by exposure of th3/+ FLCs to Tf in vitro (58 vs. 41%, P=0.001) (Figure 1B). Tf-treated th3/+ FLCs shed more TfR1 to the nuclear fraction relative to reticulocyte during enucleation (P=0.0001) (Figure 1C). Furthermore, enucleation isdecreased in vivo in th3/+ relative to WT FLCs and peripheral blood at E14.5 and normalized in th3/+ TfR1+/- double heterozygote mice (45 vs. 35%, P=0.002) (Figure 1D). Interestingly, we analyzed iron status in TfR1+/- mice revealing that serum hepcidin is increased relative to WT (323 vs. 190 ng/ml, P=0.04) despite minimally decreased serum and liver iron concentrations (no statistically significant differences) and increased Erfe expression in erythroid precursors (5-fold, P=0.04). Relative to th3/+ mice, double heterozygote mice exhibit decreased serum iron (94 vs. 133 ug/dl), non-heme liver iron (0.31 vs. 0.74 mg iron/g dry weight, P=0.02), and Erfe expression (0.3-fold, P=0.04). Although no difference is observed between double heterozygote mice and th3/+, serum hepcidin is significantly increased in double heterozygote mice compare to WT (392 vs. 190 ng/ml, P=0.01), suggesting a more appropriate hepcidin response to iron overload (Figure 1E). Taken together, we postulate that decreased TfR1 expression plays a critical role in reversing ineffective erythropoiesis by increasing enucleation and influences hepcidin regulation in an ERFE independent manner. Disclosures No relevant conflicts of interest to declare.

Measurements of serum ferritin used to predict concentrations of iron in bone marrow in anemia of chronic disease

1991 ◽  
Vol 37 (4) ◽  
pp. 560-563 ◽  
Author(s):  
J L L M Coenen ◽  
M P van Dieijen-Visser ◽  
J van Pelt ◽  
C T B M van Deursen ◽  
M M F Fickers ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Disease ◽  
Acute Phase ◽  
Serum Ferritin ◽  
Reference Method ◽  
Iron Store ◽  
Acute Phase Reactants ◽  
Anemia Of Chronic Disease ◽  
Clin Pathol ◽  
Bone Marrow Iron

Abstract We determined serum ferritin, C-reactive protein (CRP), fibrinogen, and the erythrocyte sedimentation rate (ESR) in 73 patients with anemia of chronic disease. Nomograms of CRP, ESR, or fibrinogen vs ferritin concentrations were constructed and used to estimate the iron store in bone marrow. Iron stores estimated from the nomograms were compared with the results of staining cytological bone marrow smears for iron, the reference method for evaluating iron in bone marrow. In contrast to the results of Witte et al. (Clin Chem 1985;31:1011; Am J Clin Pathol 1986;85:202-6 and 1988;90:85-7), we observed that nomograms of CRP, fibrinogen, or ESR (i.e., acute-phase reactants not influenced by changes in iron metabolism) vs ferritin are not suitable to correct for the acute-phase component of changes in ferritin concentrations. For ferritin concentrations less than 70 micrograms/L, we found that iron deficiency, as judged from bone marrow iron stain, apparently was always present.

scholarly journals Evaluation of Iron Status by Bone Marrow Iron Stain and its Correlation with Serum Iron Profile in Chronic Kidney Disease (CKD)

1970 ◽  
Vol 25 (3) ◽  
pp. 117-120 ◽  
Author(s):  
Md Mahbubur Rahman ◽  
Pradip Kumar Dutta ◽  
Mahmudul Hoque ◽  
Md Iftikher Hossain Han ◽  
Dhiman Banik ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Bone Marrow ◽  
Kidney Disease ◽  
Serum Ferritin ◽  
Serum Iron ◽  
Iron Status ◽  
Tissue Iron ◽  
Bone Marrow Iron ◽  
The Mean ◽  
Iron Profile

This observational study was done on 52 cases of predialysis chronic kidney disease (CKD) patients with chronic anaemia. The aim of the study was to determine the tissue iron status, comparison of the tissue iron with serum iron profile and justification of giving iron in chronic kidney disease (CKD) patients on the basis of serum iron profile. Bone marrow iron stain was done in each case and compared with the serum iron profile. The mean age of the patients was 46.8 ± 12.6 years and the mean haemoglobin and serum creatinine levels of the study population were 9.36 ± 2.13 gm/dl and 8.0 ± 4.2 mg/dl respectively. Stainable iron deposits were present in 40 (77%) cases. The mean serum ferritin and transferin saturation (TSAT) of the 52 cases were found to be 412.9 ng/ml and 28.3% and that for the 12 iron deficient cases were 101.8 ng/ml and 23.8%. Over all normal (>100ng/ml <500ng/ml), increased (>500ng/ml) or low (>100 ng/ml) serum ferritin was found in 28 and 15 and nine cases respectively. On the other hand, normal (>20% >50%) and low (>20%) TSAT were found in 31 and 12 cases, and high TSAT (>50%) in only nine cases. Out of the 12 cases having no evidence of stainable iron in the marrow low serum ferritin and low TSAT were found in eight (66.6%) and six (50%) cases, and high TSAT and either normal or high serum ferritin in six (50%) & four (33.3%) cases respectively. Low TSAT was also found in six (15%) cases of those having iron deposits in the marrow. It is, therefore, concluded that absence of stainable iron in the bone marrow is a better evidence of iron depletion than the serum iron profile and that serum ferritin and TSAT correlate less well with the bone marrow iron status in patient with chronic kidney disease. (J Bangladesh Coll Phys Surg 2007; 25 : 117-120)

Bone marrow iron score as an indicator for secondary iron overload in acute myeloid leukemia patients

2018 ◽  
Vol 101 (5) ◽  
pp. 591-594 ◽  
Author(s):  
Marlijn Hoeks ◽  
Marit van der Pol ◽  
Rutger Middelburg ◽  
Dorothea Evers ◽  
Marian van Kraaij ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Iron Overload ◽  
Myeloid Leukemia ◽  
Secondary Iron Overload ◽  
Bone Marrow Iron ◽  
Acute Myeloid

scholarly journals MFehi adipose tissue macrophages compensate for tissue iron perturbations in mice

2018 ◽  
Vol 315 (3) ◽  
pp. C319-C329 ◽  
Author(s):  
Merla J. Hubler ◽  
Keith M. Erikson ◽  
Arion J. Kennedy ◽  
Alyssa H. Hasty
Keyword(s):  
Adipose Tissue ◽  
Iron Overload ◽  
Iron Content ◽  
Iron Homeostasis ◽  
Dietary Iron ◽  
Iron Cycling ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Adipose Tissue Macrophages ◽  
Tissue Iron

Resident adipose tissue macrophages (ATMs) play multiple roles to maintain tissue homeostasis, such as removing excess free fatty acids and regulation of the extracellular matrix. The phagocytic nature and oxidative resiliency of macrophages not only allows them to function as innate immune cells but also to respond to specific tissue needs, such as iron homeostasis. MFehi ATMs are a subtype of resident ATMs that we recently identified to have twice the intracellular iron content as other ATMs and elevated expression of iron-handling genes. Although studies have demonstrated that iron homeostasis is important for adipocyte health, little is known about how MFehi ATMs may respond to and influence adipose tissue iron availability. Two methodologies were used to address this question: dietary iron supplementation and intraperitoneal iron injection. Upon exposure to high dietary iron, MFehi ATMs accumulated excess iron, whereas the iron content of MFelo ATMs and adipocytes remained unchanged. In this model of chronic iron excess, MFehi ATMs exhibited increased expression of genes involved in iron storage. In the injection model, MFehi ATMs incorporated high levels of iron, and adipocytes were spared iron overload. This acute model of iron overload was associated with increased numbers of MFehi ATMs; 17% could be attributed to monocyte recruitment and 83% to MFelo ATM incorporation into the MFehi pool. The MFehi ATM population maintained its low inflammatory profile and iron-cycling expression profile. These studies expand the field’s understanding of ATMs and confirm that they can respond as a tissue iron sink in models of iron overload.

Apotransferrin Injection Leads to More Effective Erythropoiesis in β-Thalassemic Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 276-276
Author(s):  
Yelena Z. Ginzburg ◽  
Anne C. Rybicki ◽  
Sandra M. Suzuka ◽  
Leni von Bonsdorff ◽  
Mary E. Fabry ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Binding Capacity ◽  
Globin Gene ◽  
Transferrin Saturation ◽  
Dry Weight ◽  
Ineffective Erythropoiesis ◽  
Erythroid Precursor ◽  
Hepcidin Expression ◽  
Erythroid Precursors

Abstract β-thalassemia is a disease resulting from a β-globin gene mutation which leads to less β-globin, expanded and ineffective erythropoiesis, and anemia. Additionally, mature red blood cells have a shortened survival. Although the degree of anemia varies, from severe transfusion-dependence to only an increase in iron absorption in the gut to maintain hemoglobin levels, all thalassemic patients develop some degree of iron overload. In a previous study using β-thalassemic mice, we were able to induce iron overload using iron dextran injections and demonstrated an increase in hemoglobin with increased reticulocytosis and an expansion of extramedullary erythropoiesis in the liver and spleen. The fact that iron administration reduced anemia in β-thalassemic mice was surprising. Since patients with β-thalassemia have ample iron supply, we hypothesized that part of the anemia in β-thalassemia may result from a maldistribution of iron as a consequence of insufficient circulating transferrin to deliver iron for erythropoiesis. In the present study, we analyzed the effect of intraperitoneal human apotransferrin injections on markers of hematopoiesis and iron metabolism in thalassemic mice. We used three different doses of apotransferrin - 5mg, 10mg, and 30mg - daily, for a 10 day course. Mice with β-thalassemia intermedia (Hbbth1/th1) were compared with age and gender matched control C57BL/6J mice. Although no increase in hemoglobin was observed, the reticulocyte count decreased after apotransferrin injections (2975±125 x 109 vs. 1636±130 x 109 cells/L, P=2.29 x 10−5). The efficiency of erythropoiesis, as measured by red cell to reticulocyte ratio, increased after apotransferrin injections (0.029±0.002 vs. 0.007±0.0007, P=0.0002), confirming that more red cells circulate as a result of each maturing erythroid precursor. We were able to demonstrate that apotransferrin is effective in increasing transferrin iron binding capacity (TIBC) (739.5±98.4 vs. 419.1±18.3 mg/dL, P=0.002) without changing the transferrin saturation (23.0±7.1 vs. 34.9±4.2%, P=0.15) in our mice. Apotransferrin injections also resulted in a reduction of iron deposition in the liver (5.49±0.48 vs. 11.08±1.24 mg/g dry weight, P=0.003) and heart (1.25±0.18 vs. 2.26±0.26 mg/g dry weight, P=5.7 x 10−5) of Hbbth1/th1 mice without changes in labile plasma iron levels. Using flow cytometry, we demonstrated an increase in erythroid precursors in the bone marrow of Hbbth1/th1 mice (68.7±1.5 vs. 56.5±3.96% ter119+ precursors, P=0.01) but a decrease in the spleen (41.05±3.16 vs. 60.95±8.3% ter119+ precursors, P=0.03) compared to baseline. Lastly, liver hepcidin expression was progressively suppressed with increasing transferrin dose in our mice. Taken together, this data strongly suggests that exogenous apotransferrin is able to mobilize stored iron for production of erythroid precursors in the bone marrow; this process leads to hepcidin suppression. Diseases of ineffective erythropoiesis, in which expanding erythropoiesis may be limited by the iron delivery system to maintain hemoglobin production, may be a result of insufficient transferrin and relative iron deficiency. The significance of our current findings has potential broad implications for the mobilization of stored iron for use in erythropoiesis in many diseases in which iron overload co-exists with anemia such as β-thalassemia, sideroblastic anemia, and the myelodysplastic syndromes.

scholarly journals Bone Marrow Iron Assessment By MRI-R2* and Its Relation to Deferasirox Treatment in Patients with Iron Overload

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3358-3358
Author(s):  
Regine Grosse ◽  
Suzan Acar ◽  
Bjoern Schoennagel ◽  
Roland Fischer ◽  
Jin Yamamura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Content ◽  
Chelation Therapy ◽  
Hereditary Hemochromatosis ◽  
Iron Loading ◽  
Bone Marrow Iron ◽  
Vertebral Bone Marrow

Abstract Objective: Patients with iron overload suffer from different organ damage due to increased iron concentration. Iron overload in the bone marrow and the influence of iron chelation therapy on bone marrow iron content may play an additional role in these patients and is until now not well examined. Material and Methods: We performed MRI-R2* measurements in the vertebral bone marrow using water-fat chemical shift relaxometry for estimation of iron and fat content in comparison to hepatic and splenic iron concentrations and serum ferritin in patients with iron overload due to hereditary hemochromatosis (HHC) and patients with siderosis due to red blood cell transfusions and /or iron loading anemia. 112 patients with iron overload, mean age: 32 y (transfusion dependent thalassemia major (TM) n=65, Diamond-Blackfan anemia (DBA) n=12, HHC n=10, iron loading anemia (EA) n=7, transfusion siderosis n=12 and stem cell transplantation n=6) and 14 control subjects underwent MRI for determination of the transverse relaxation rate R2*assessed from ROI based signal intensities of one transversal slice (10mm) through the liver, spleen, and mid-vertebral bone marrow. Breathhold water-fat relaxometry (12 echo times, TE=1.3-26ms, FA=20°, bandwidth=1955Hz/px) was performed to determine apparent fat contents (aFC) and bone marrow R2*. Additionally, serum ferritin values were assessed. In 67 patients with TM under chelation therapy with Deferasirox (DFX) we compared R2* bone marrow iron content with the ratio of the chelator dose rate (Deferasirox, [mmol/d]) to the total liver iron (LivFe = LIC*volume [g-Fe]). Results: Relative to controls (n=14, R2* = 95s-1) and HHC (n=10, R2* = 95s-1), median bone marrow R2* rates were significantly increased in patients with TM (n=65, R2* = 398s-1, p<10-4) or DBA (n=12, R2* = 252s-1, p = 0.005). R2* of the bone marrow significantly correlated with serum ferritin (rS=0.52, p<10-4), splenic R2* (rS=0.43, p<10-4), cardiac R2* (rS=0.43, p<10-4), and hepatic R2* (rS=0.37, p<10-4). No significant correlation of aFC with marrow R2* could be obtained. The bone marrow iron content was higher in patients with a low Deferasirox (DFX) dose. A DFX dose > 150 (mmol/d)/g-Fe was a negativ predictor for increased bone marrow iron content (R2* > 700 1/s), but a significant correlation couldn't be found (r = 0,077), probably due to the low number of patients. The efficacy dose of DFX for a low bone marrow iron content seems to lay between a dose of 1mmol/d (18mg/d) and 2,5 mmol/d (45mg/d). A DFX dose > 2,5 mmol/d didn't seem to increase the efficacy. Table 1. Diagnosis (n) Age Median (IQR) KM R2* [s-1 ] Median (IQR) KM R2* 95 % range Control group (14) 29.8 (26.0) 95 (43) 62 - 134 TM ( 65) 30.6 (16.2) 398 (455) 73 - 1213 HH (10) 56.4 (9.3) 95 (40) 61 - 270 EA (7) 46.6 (24.8) 191 (93) 159 - 490 DBA (12) 27,6 (14.6) 252 (250) 62 - 652 TS(12) 32.3 (46.2) 322 (304) 116 - 607 BMT (6) 20 (20.8) 285 (342) 105 - 470 Conclusion: Water-fat chemical shift relaxometry allows precise determination of bone marrow R2* rates and estimation of the apparent fat content, which may add additional information to these patients. Patients with transfusion related iron overload have significant higher bone marrow iron content than patients with iron overload due to hereditary hemochromatosis. DFX in an adäquat dose seem to prefent bone marrow iron overload. Disclosures Grosse: Swedish Orphan Biovitrum: Honoraria; Novartis Oncology: Honoraria, Research Funding.

scholarly journals Increased Bone Marrow Iron at Diagnosis Is Associated with Inferior Prognosis in Patients with Myelodysplastic Syndromes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3700-3700
Author(s):  
Annika Kasprzak ◽  
Sandra Becker ◽  
Martina Rudelius ◽  
Corinna Strupp ◽  
Kathrin Nachtkamp ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Median Survival ◽  
Myelodysplastic Syndromes ◽  
Iron Uptake ◽  
Research Funding ◽  
Blue Staining ◽  
Prognostic Impact ◽  
Iron Stores ◽  
Bone Marrow Iron

Abstract Introduction: Iron storage in patients (pts) with myelodysplastic syndromes at the time of diagnosis may vary from normal to iron overload. Even before the first blood transfusion, storage iron can be increased due to down-regulation of hepcidin and subsequent increase in duodenal iron uptake. Iron overload is known to worsen the prognosis of MDS patients, partly due to iron-related organ damage after long-term transfusion therapy, and partly due to an increased risk of infections. However, it is unclear whether increased storage iron at the time of diagnosis already has a prognostic influence. We assessed bone marrow iron stores at the time of MDS diagnosis and correlated them with clinical outcome. Methods: In a retrospective analysis of 3762 adult MDS patients from the Düsseldorf MDS Registry, Prussian blue staining of marrow smears was performed in our cytology lab to assess iron stores according to the following categories: normal or decreased iron stores versus increased iron stores versus iron overload. Patients were followed up for survival and AML evolution until June 2021. Median time of follow-up was 20 months. 67.4% of the patients died during the course of the disease. Results: The study included 3.762 adult patients who received their initial diagnosis of MDS between 1970 and 2021. 58% were diagnosed as non-blastic MDS ( MDS SLD (RS) (n=240), MDS MLD (RS) (n=350), MDSdel(5q) (n=107), and MDS-U (n=25). Iron stores were decreased in 8% of the patients, normal in 44%, increased in 41%, and strongly increased in 7% (massive iron overload). In 282 cases, histologic assessment of storage iron was available. When comparing cytologic and histologic assessment, we found a strong correlation (p&lt;0.0005), since 87% of the patients with increased iron on cytomorphology also showed increased iron as assessed by histopathology. However, 37% of the patients who cytologically showed normal iron stores, were reported to have slightly increased iron as assessed by histopathology. Median and mean serum ferritin values of patients with normal or decreased iron stores were 295 and 629 µg/l, respectively, as compared to 548 and 902 µg/l, respectively, in patients with increased iron stores. The cumulative risk of AML evolution was not associated with the results of iron staining. Regarding survival, we found that patients with decreased or normal storage iron had a median survival of 31 months, whereas those with increased iron had a median survival of 28 months (p=0.007). Focusing on patients with non-blastic MDS, the difference was not significant (46 vs 44 ms). However, patients who presented as EB I (n=435), EBII (n=510), AML MRC (n=264), CMML I (n=254), or CMML II (n=77), showed a prognostic impact of storage iron; patients with increased iron had a median survival of 11 months, as compared to 16 months in patients with normal or decreased iron (p&lt;0.0005). Conclusion: Increased tissue iron in the bone marrow at the time of diagnosis is associated with inferior survival in patients with MDS, primarily in patients with higher risk MDS. At diagnosis, patients are not yet transfusion-dependent. This suggests that increased iron reflects a prolonged period of increased duodenal iron uptake as a consequence of ineffective erythropoiesis. Therefore, increased marrow iron at the time of MDS diagnosis seems to be a surrogate parameter of hematopoietic insufficiency, which is the real cause of inferior prognosis. Disclosures Nachtkamp: Jazz: Honoraria; Bsh medical: Honoraria; Celgene: Other: Travel Support. Gattermann: Novartis: Honoraria; Takeda: Research Funding; Celgene: Honoraria. Germing: Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document