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1.
Data-driven physiologic thresholds for iron deficiency associated with hematologic decline.
Foy, BH, Li, A, McClung, JP, Ranganath, R, Higgins, JM
American journal of hematology. 2020;(3):302-309
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Abstract
Iron-deficiency contributes to a ∼50% of anemia prevalence worldwide, but reference intervals for iron status tests are not optimized for anemia diagnosis. To address this limitation, we identified the serum ferritin (SF) thresholds associated with hematologic decline in iron-deficient patients, and the SF thresholds from which an SF increase was associated with hematologic improvement. Paired red blood cell and SF measurements were analysed from two adult cohorts at Massachusetts General Hospital (MGH), from 2008-2011 (N = 48 409), and 2016-2018 (N = 10 042). Inter-patient measurements in the first cohort were used to define optimal SF thresholds based on the physiologic relationship between SF and red cell measurements. Intra-patient measurements (1-26 weeks apart) in the second cohort were used to identify SF thresholds from which an SF increase was associated, with an increase in red cell measurements. The identified optimal SF thresholds varied with age, sex and red cell measure. Thresholds associated with a ∼5% decline in red cell index were typically in the range 10-25 ng/mL. Thresholds for younger women (18-45 year) were ∼5 ng/mL lower than for older women (60-95 years), and ∼10 ng/mL lower than for men. Thresholds from which a subsequent increase in SF was associated with a concomitant increase in red cell measure showed similar patterns: younger women had lower thresholds (∼15 ng/mL) than older women (∼25 ng/mL), or men (∼35 ng/mL). These results suggest that diagnostic accuracy may be improved by setting different SF thresholds for younger women, older women, and men. This study illustrates how clinical databases may provide physiologic evidence for improved diagnostic thresholds.
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Evaluation of Efficacy, Safety, and Satisfaction Taking Deferasirox Twice Daily Versus Once Daily in Patients With Transfusion-Dependent Thalassemia.
Karimi, M, Haghpanah, S, Bahoush, G, Ansari, S, Azarkeivan, A, Shahsavani, A, Bazrafshan, A, Jangjou, A
Journal of pediatric hematology/oncology. 2020;(1):23-26
Abstract
OBJECTIVE Deferasirox is a once-daily oral iron-chelation agent approved by the US Food and Drug Administration in November 2005. The authors aimed to evaluate efficacy, safety, and satisfaction of patients regarding twice-daily dose of deferasirox in patients with thalassemia who are resistant to once-daily regimen. METHODS In this historical cohort multicenter study, 34 patients with beta-thalassemia major resistant or intolerant to once-daily dose of deferasirox (35 mg/kg/d) were investigated in 2016. Patients were registered at 3 thalassemia referral centers in Shiraz, southern Iran and Tehran, the capital of Iran. All patients were followed for 1 year and monitored by regular physical examination, laboratory data, serum ferritin levels, and heart and liver T2 magnetic resonance imaging. RESULTS Mean age of thalassemia patients was 25.6±8.1 (8 to 40) years, including 22 female individuals and 12 male individuals. Serum ferritin levels significantly decreased during the study period (2021±955 at baseline vs. 1228±894 at the end of the study, P<0.001). Liver T2 magnetic resonance imaging of the patients demonstrated a significant improvement during the study. 73.3% of patients showed normal values at the end of study compared with 28.1% at the baseline (P<0.001). Drug side effects were reported only in 2 patients (5.8%) including 1 patient with abdominal pain and 1 with leukopenia and thrombocytopenia. CONCLUSIONS It seems that deferasirox can be used with increased dose and twice daily with acceptable efficacy in unresponsive or intolerant thalassemia patients to once-daily dose. Close monitoring of the patients is necessary to detect and manage any possible adverse events.
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The association of elevated serum ferritin concentration in early pregnancy with gestational diabetes mellitus: a prospective observational study.
Cheng, Y, Li, T, He, M, Liu, J, Wu, K, Liu, S, Ma, Z, Lu, J, Zhang, Q, Cheng, H
European journal of clinical nutrition. 2020;(5):741-748
Abstract
BACKGROUND/OBJECTIVES The results linking body iron stores to the risk of gestational diabetes mellitus (GDM) are conflicting. We aimed to measure the serum ferritin level of women in early pregnancy and evaluate the risk of GDM in a Chinese urban population. SUBJECTS/METHODS In total, 851 pregnant women between 10 and 20 weeks of gestation took part in the prospective, observational study conducted. The women were divided into four groups by quartiles of serum ferritin levels (Q1-4). Their blood samples were collected and assayed for several biochemical variables at the beginning of the study, and the women were followed up with a 75-g oral glucose tolerance test at 24-28 weeks of gestation. RESULTS The participants had an average serum ferritin concentration of 65.67 μg/L. GDM prevalence within each serum ferritin quartile was 9.4%, 14.6%, 18.8% and 19.3%, respectively, (P = 0.016). The odds ratio for GDM in the ferritin Q2-4 was 1.64 (CI: 0.90-2.99), 2.23 (CI: 1.26-3.96) and 2.31 (CI: 1.30-4.10), compared with Q1, respectively. This association persisted after adjusting for potential confounders factors. In addition, in Q4, pregnant women with a pre-pregnancy body mass index ≥24 kg/m2, maternal age ≤35 years old or haemoglobin≥ 110 g/L did have an increased risk of developing GDM. CONCLUSIONS Elevated serum ferritin concentrations in early gestation are associated with an increased risk of GDM, especially in pregnant women who have a high baseline iron storage status with no anaemia or who are overweight/obese. Individual iron supplementation should be considered to minimize the risk of GDM.
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Iron Homeostasis and Ferritin in Sepsis-Associated Kidney Injury.
McCullough, K, Bolisetty, S
Nephron. 2020;(12):616-620
Abstract
Sepsis associated acute kidney injury (SA-AKI) is a common clinical syndrome that occurs among hospitalized patients and significantly impacts mortality. Furthermore, survival after sepsis is intricately dependent on recovery of kidney function. In this review, we discuss the role of iron imbalance in mediating the pathogenic events during sepsis. Intracellular ferritin serves as a repository for iron and prevents iron-mediated injury and may limit the availability of iron to pathogens. Circulating levels of ferritin also increase during sepsis and often correlate with severity of sepsis. Herein, we examine preclinical and clinical data and discuss recent findings that suggest immunomodulatory roles for ferritin. We also discuss the possible mechanistic roles for ferritin in mitigating the pathogenic sequelae of sepsis and highlight current gaps in knowledge.
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Low transferrin saturation (TSAT) and high ferritin levels are significant predictors for cerebrovascular and cardiovascular disease and death in maintenance hemodialysis patients.
Kuragano, T, Joki, N, Hase, H, Kitamura, K, Murata, T, Fujimoto, S, Fukatsu, A, Inoue, T, Itakura, Y, Nakanishi, T
PloS one. 2020;(9):e0236277
Abstract
Patients with high serum ferritin and low transferrin saturation (TSAT) levels could be considered as presenting with dysutilization of iron for erythropoiesis. However, the long-term safety of iron administration in these patients has not been well established. An observational multicenter study was performed over 3 years. In 805 patients undergoing maintenance hemodialysis (MHD), we defined dysutilization of iron for erythropoiesis in patients with lower TSAT (<20%) and higher ferritin (≥100 ng/mL) levels. A time-dependent Cox hazard model was used for the evaluation of the association between dysutilization of iron for erythropoiesis and adverse events and survival. Patients with low TSAT levels showed an increased risk of cerebrovascular and cardiovascular disease (CCVD) and death compared to patients with normal or higher TSAT levels. Patients with low ferritin and high TSAT levels had a significantly lower risk of CCVD and death compared with patients with high ferritin and low TSAT levels. Higher TSAT levels were associated with male gender, age, the absence of diabetes, low levels of high-sensitivity CRP, and low β2 microglobulin levels, but not with intravenous iron administration or ferritin levels. Although patients with low TSAT levels had a significantly higher risk of CCVD or death, high TSAT levels were not linked with iron administration. Patients, who were suspected of dysutilization of iron for erythropoiesis, had a higher risk of CCVD and death. The administration of iron should be performed cautiously for improving TSAT levels, as iron administration could sustain TSAT levels for a short term.
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Iron deficiency markers in patients undergoing iron replacement therapy: a 9-year retrospective real-world evidence study using healthcare databases.
Cacoub, P, Nicolas, G, Peoc'h, K
Scientific reports. 2020;(1):14983
Abstract
The diagnosis and treatment of iron deficiency is a primary public health goal. This study aimed to make an inventory of the use of biomarkers to assess the iron supply in patients given iron replacement therapy. A retrospective longitudinal real-world study of a cohort of patients receiving iron replacement therapy was conducted using data from healthcare coverage databases between January 2006 and December 2015 in France. The frequency of oral or intravenous iron treatment episodes preceded and/or followed by a biological assessment of iron deficiency was described. We then differentiate patients with or without chronic inflammatory diseases, which could impact the prescription. The evolution between 2006 and 2015 was also studied. The 96,724 patients received an average of 4.9 administrations of iron per patient, corresponding to 1.7 treatment episodes. In one-third of treatment episodes (34.6%), patients had a pre-treatment biological assessment, 15.5% a post-treatment assessment, and 7.3% both. The post-treatment measure of iron supply markers (i.e., Ferritin and transferrin saturation) was more frequent in patients suffering from chronic inflammatory diseases than in those without underlying chronic condition (22.6% to 41.0% vs. 3.1%; p < 0.0001). Serum ferritin was measured 30 times more than transferrin saturation measurements. The use of both tests increased steadily during the study period, although remaining low. Despite the recommendations, biological assessments of iron status are seldom prescribed and/or performed in the context of a pre- or post-treatment assessment, although more frequently realized in patients with chronic inflammatory diseases.
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Iron Serum Markers Profile in Frontotemporal Lobar Degeneration.
De Luca, A, Fostinelli, S, Ferrari, C, Binetti, G, Benussi, L, Borroni, B, Rossi, L, Rongioletti, M, Ghidoni, R, Squitti, R
Journal of Alzheimer's disease : JAD. 2020;(4):1373-1380
Abstract
Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative syndrome. Defects of copper (Cu) and iron (Fe) homeostasis are involved in the development of several neurodegenerative diseases and their homeostasis is interconnected by the Cu-protein ceruloplasmin (Cp), responsible for Fe oxidative state. In this study we assessed Fe, transferrin (Trf), ferritin, Cp specific activity (eCp/iCp), Cp/Trf ratio, and Trf saturation in 60 FTLD patients and 43 healthy controls, and discussed the results in relation to Cu homeostasis. The significant decrease of the eCp/iCp in the FTLD patients supports the involvement of Fe imbalance in the onset and progression of FTLD.
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Intravenous Iron sucrose and change in hemoglobin, ferritin, and oxidative stress markers among moderately anemic pregnant women attending a secondary care level Hospital in Northern India.
Jacob, OM, Kant, S, Haldar, P, Kaur, R, Dadhwal, V, Prakash, S
Indian journal of public health. 2020;(1):11-16
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Abstract
BACKGROUND Intravenous iron is associated with oxidative stress, and very few studies have assessed change in oxidative stress markers post infusion. OBJECTIVES The study aimed to measure the change in levels of hemoglobin (Hb), serum ferritin, and select oxidative stress markers (malondialdehyde [MDA], superoxide dismutase [SOD], and ferric reducing ability of plasma [FRAP]) 4 weeks following the administration of intravenous iron sucrose (IVIS) among moderately anemic pregnant women who were attending a secondary-level health-care facility, Haryana, North India. METHODS An observational study was conducted (May 2016 to Jan 2018) among pregnant women receiving intravenous iron sucrose i.e., IVIS (300 mg per dose) diluted in 300 mL of normal saline over 20-45 min and were followed up for a period of 4 weeks after the last dose of IVIS (end line). The study outcomes were measured in the levels of Hb, serum ferritin, MDA, SOD, and FRAP from the baseline to the end line. RESULTS The mean (95% confidence interval) change in the Hb and serum ferritin level 4 weeks after the last dose of IVIS was an increase of 2.5 (2.1-3.0) g/dL (P < 0.001) and 63.0 (44.7-81.3) ng/mL (P < 0.001), respectively. There were no significant changes (baseline to end line) in mean (standard deviation [SD]) MDA level and mean (SD) FRAP level. The mean (SD) SOD level declined significantly (2.2 [0.4] U/mL to 1.6 [0.5] U/mL [P < 0.001]). No life-threatening adverse events were encountered during the study. CONCLUSION IVIS was well tolerated and effective in treating moderate anemia in pregnancy. Body iron store was replenished following IVIS administration. There was no increase in oxidative stress following IVIS therapy.
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Efficacy and safety of high-dose intravenous iron as the first-choice therapy in outpatients with severe iron deficiency anemia.
Jericó, C, Beverina, I, Quintana-Diaz, M, Salvadori, U, Melli, C, Rondinelli, MB, Recasens, V, Brando, B, Garcia-Erce, JA
Transfusion. 2020;(7):1443-1449
Abstract
BACKGROUND Asymptomatic severe iron deficiency anemia is a common finding in subjects admitted to the outpatient anemia clinic. Although the condition can be easily be reversed with intravenous iron (IVI) therapy and several guidelines have suggested a restrictive threshold for using transfusion in hemodynamically stable patients, transfusion is often the rule in clinical practice. This study describes clinical practice results of IVI therapy without transfusion. STUDY DESIGN AND METHODS In this multicenter retrospective observational study, data of severely anemic outpatients treated only with high-dose IVI with ferric carboxymaltose were collected. Inclusion criteria were hemoglobin (Hb) level of less than 7.0 g/dL and ferritin level of less than 30 ng/mL or mean corpuscular volume of less than 75 fL. RESULTS Overall, 303 patients referred to the anemia clinic mainly from primary health care centers (46.2%) or the emergency department (28.7%) met the inclusion criteria. Median (interquartile range [IQR]) age was 47 (37-62) years and 84.5% were female. The median (IQR) Hb concentration at first visit was 6.5 (6.1-6.8) g/dL, 64 patients (21.1%) presented with a Hb level of less than 6.0 g/dL at diagnosis, and 11 of them (3.6%) had extreme anemia (Hb ≤ 5 g/dL). Gynecologic and gastroenteric bleeding were the main cause. After a mean IV administration of 1500 mg of iron, the Hb increased by a median of 5.7 g/dL. Thirteen patients experienced only mild side effects. CONCLUSIONS In chronic very severe sideropenic anemias, third-generation IVI is effective and safe for quick correction and avoidance of red blood cell transfusion. These results suggest that more specific guidelines for this clinical setting are warranted.
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The vicious cycle between ferritinophagy and ROS production triggered EMT inhibition of gastric cancer cells was through p53/AKT/mTor pathway.
Xu, Z, Feng, J, Li, Y, Guan, D, Chen, H, Zhai, X, Zhang, L, Li, C, Li, C
Chemico-biological interactions. 2020;:109196
Abstract
Cancer metastasis and resistance for chemotherapeutic agent correlate with epithelial-mesenchymal transition (EMT), while ROS production also involves in the EMT process, However, how autophagy mediated ROS production affects EMT remains unclear. Previous study showed that DpdtC (2,2'-di-pyridylketone hydrazone dithiocarbamate) could induce ferritinophagy in HepG2 cell. To insight into more details that how ferritinophagy affects cellular feature, the SGC-7901and BGC-823 gastric cancer cell lines were used. Interestingly DpdtC treatment resulted in EMT inhibition and was ROS dependent. Similar situation occurred in TGF-β1 induced EMT model, supporting that DpdtC was able to inhibit EMT. Next the ability of DpdtC in ferritinophagy induction was further evaluated. As expected, DpdtC induced ferritinophagy in the absence and presence of TGF-β1. The correlation analysis revealed that an enhanced ferritinophagic flux contributed to the EMT inhibition. In addition, ferritinophagy triggers Fenton reaction, resulting in ROS production which give rise of p53 response, thus the role of p53 was further investigated. DpdtC treatment resulted in upregulation of p53, but, the addition of p53 inhibitor, PFT-α could significantly neutralize the action of DpdtC on ferritinophagy induction and EMT inhibition. Furthermore, autophagy inhibitors or NAC could counteract the action of DpdtC, indicating that ferrtinophagy-mediated ROS played an important role in the cellular events. In addition to upregulation of p53, its down-stream targets, AKT/mTor were also downregulated, supporting that DpdtC induced EMT inhibition was achieved through ferritinophagy-ROS vicious cycle mediated p53/AKT/mTor pathway. And the activation of ferritinophagic flux was the dominant driving force in action of DpdtC in gastric cancer cells.