scholarly journals COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review

2020 ◽  
Vol 10 (2) ◽  
Author(s):  
Attilio Cavezzi ◽  
Emidio Troiani ◽  
Salvatore Corrao
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Narrative Review ◽  
Capillary Barrier ◽  
Cell Tissue ◽  
Clinical Syndromes ◽  
Systemic Hypoxia ◽  
Hemoglobin Molecule ◽  
Hypoxic State ◽  
Additional Role

Coronavirus disease-19 (COVID-19) has been regarded as an infective-inflammatory disease, which affects mainly lungs. More recently, a multi-organ involvement has been highlighted, with different pathways of injury. A hemoglobinopathy, hypoxia and cell iron overload might have a possible additional role. Scientific literature has pointed out two potential pathophysiological mechanisms: i) severe acute respiratory syndrome-coronavirus-2 (SARS-CoV- 2) interaction with hemoglobin molecule, through CD147, CD26 and other receptors located on erythrocyte and/or blood cell precursors; ii) hepcidin-mimetic action of a viral spike protein, inducing ferroportin blockage. In this translational medicinebased narrative review, the following pathologic metabolic pathways, deriving from hemoglobin denaturation and iron metabolism dysregulation, are highlighted: i) decrease of functioning hemoglobin quote; ii) iron overload in cell/tissue (hyperferritinemia); iii) release of free toxic circulating heme; iv) hypoxemia and systemic hypoxia; v) reduction of nitric oxide; vi) coagulation activation; vii) ferroptosis with oxidative stress and lipoperoxidation; viii) mitochondrial degeneration and apoptosis. A few clinical syndromes may follow, such as pulmonary edema based on arterial vasoconstriction and altered alveolo-capillary barrier, sideroblastic-like anemia, endotheliitis, vasospastic acrosyndrome, and arterio- venous thromboembolism. We speculated that in COVID-19, beyond the classical pulmonary immune-inflammation view, the occurrence of an oxygen-deprived blood disease, with iron metabolism dysregulation, should be taken in consideration. A more comprehensive diagnostic/therapeutic approach to COVID-19 is proposed, including potential adjuvant interventions aimed at improving hemoglobin dysfunction, iron over-deposit and generalized hypoxic state.

Iron Metabolism in the Human Body and Setting its Hygienic Limits for Drinking Water. Review. Part 2

2020 ◽  
Vol 99 (5) ◽  
pp. 504-508
Author(s):  
Natalija A. Egorova ◽  
N. V. Kanatnikova
Keyword(s):  
Oxidative Stress ◽  
Drinking Water ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Subcutaneous Tissue ◽  
Allergic Diseases ◽  
The Body ◽  
Urogenital System ◽  
High Iron Content ◽  
Labile Iron Pool

Iron is an assential element for the growth, division, differentiation and functioning of any cell in the body. Iron is virtually important for human and danger at the same time, because with excessive accumulation it causes oxidative stress with formation of highly active oxygen radicals and reactive form of nitrogen that can destroy cell membranes, proteins, nucleic acids, reduce cell viability, with, according to modern concepts, can contribute to the development of many diseases (cardiovascular, rheumatic, gastrointestinal, neurodegenerative, oncological, metabolic and others), and also accelerate the aging process. Part 1 of this review discussed the issues of iron metabolism in human, including its regulation at the cellular and systemic levels, the intake, transport, use, accumulation and export of iron in cells, the role of the labile iron pool in the cytoplasm of cells and plasma non-transferrin bound iron. Data are provided on the causes, frequency and significance of iron overload in the formation of free radicals and the development of oxidative stress. Part 2 of the review provides information on diseases associated with iron overload as well as information on ferroptosis - a new type of iron-dependent regulated cell death. Attention is paid to the works of domestic authors, where it was found that prolonged use of drinking water with a high iron content is unfavorable for the population and leads to an increase in the overall incidence, the development of the diseases of the blood, skin and subcutaneous tissue, musculoskeletal system, digestive system, urogenital system, and allergic diseases. Separate publications are cited on the possibility of a negative effect of iron at concentrations in water of 0.3 mg/l and lower. The material of the review emphasizes the preventive significance of caution attitude to regulating iron in the water in the Russian Federation, where 1/3 of the population uses iron-containing water for drinking, and substantiate the feasibility of establishing a hygienic limit for iron in water not higher than 0.3 mg/l.

scholarly journals The Interplay between Drivers of Erythropoiesis and Iron Homeostasis in Rare Hereditary Anemias: Tipping the Balance

2021 ◽  
Vol 22 (4) ◽  
pp. 2204
Author(s):  
Simon Grootendorst ◽  
Jonathan de Wilde ◽  
Birgit van Dooijeweert ◽  
Annelies van Vuren ◽  
Wouter van Solinge ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Significant Problem ◽  
Blood Transfusions ◽  
Intrinsic Defects ◽  
Chronic Anemia ◽  
Erythroid Development ◽  
Disease Specific

Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due to unavailability of iron for erythropoiesis. Whereas iron overload generally is a well-recognized complication in patients requiring regular blood transfusions, it is also a significant problem in a large proportion of patients with RHA that are not transfusion dependent. This indicates that RHA share disease-specific defects in erythroid development that are linked to intrinsic defects in iron metabolism. In this review, we discuss the key regulators involved in the interplay between iron and erythropoiesis and their importance in the spectrum of RHA.

scholarly journals Iron age: novel targets for iron overload

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 216-221 ◽  
Author(s):  
Carla Casu ◽  
Stefano Rivella
Keyword(s):  
Iron Overload ◽  
Iron Age ◽  
Iron Metabolism ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Therapeutic Approaches ◽  
Hepcidin Expression ◽  
Beneficial Effects ◽  
Excess Iron ◽  
Major Factors

Abstract Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by β-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in β-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in β-thalassemia.

Hepcidin in Iron Homeostasis: Diagnostic and Therapeutic Implications in Type 2 Diabetes Mellitus Patients

2017 ◽  
Vol 138 (4) ◽  
pp. 183-193 ◽  
Author(s):  
Sintayehu Ambachew ◽  
Belete Biadgo
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Diabetic Patients ◽  
Hepatitis C Infection ◽  
Body Iron

The prevalence of type 2 diabetes is increasing in epidemic proportions worldwide. Evidence suggests body iron overload is frequently linked and observed in patients with type 2 diabetes. Body iron metabolism is based on iron conservation and recycling by which only a part of the daily need is replaced by duodenal absorption. The principal liver-produced peptide called hepcidin plays a fundamental role in iron metabolism. It directly binds to ferroportin, the sole iron exporter, resulting in the internalization and degradation of ferroportin. However, inappropriate production of hepcidin has been shown to play a role in the pathogenesis of type 2 diabetes mellitus and its complications, based on the regulation and expression in iron-abundant cells. Underexpression of hepcidin results in body iron overload, which triggers the production of reactive oxygen species simultaneously thought to play a major role in diabetes pathogenesis mediated both by β-cell failure and insulin resistance. Increased hepcidin expression results in increased intracellular sequestration of iron, and is associated with the complications of type 2 diabetes. Besides, hepcidin concentrations have been linked to inflammatory cytokines, matriptase 2, and chronic hepatitis C infection, which have in turn been reported to be associated with diabetes by several approaches. Either hepcidin-targeted therapy alone or as adjunctive therapy with phlebotomy, iron chelators, or dietary iron restriction may be able to alter iron parameters in diabetic patients. Therefore, measuring hepcidin may improve differential diagnosis and the monitoring of disorders of iron metabolism.

scholarly journals Body iron metabolism and pathophysiology of iron overload

2008 ◽  
Vol 88 (1) ◽  
pp. 7-15 ◽  
Author(s):  
Yutaka Kohgo ◽  
Katsuya Ikuta ◽  
Takaaki Ohtake ◽  
Yoshihiro Torimoto ◽  
Junji Kato
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Body Iron

Expression of Genes Regulating Iron Metabolism in Hepatocyte Cell-Line HepG2 Induced by Sera from MDS Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4612-4612 ◽  
Author(s):  
Laura Breda ◽  
Hussam Ghoti ◽  
Stefano Rivella ◽  
Gideon Rechavi ◽  
Ioav Cabantchik ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Hepg2 Cells ◽  
Serum Iron ◽  
Refractory Anemia ◽  
Serum Samples ◽  
Group I ◽  
Plasma Factor ◽  
Normal Expression ◽  
Plasma Factors

Abstract Liver expression of hepcidin, a key factor in the regulation of iron absorption and recycling, responds commensurately to plasma iron levels. However, in thalassemic humans and mouse models, despite the overt iron overload found, there is a low expression of liver hepcidin and low levels in urine. We have recently shown that hepcidin expression induced by plasma factors in hemochromatosis is overriden in thalassemic patients (Weiser-Stern et al, Brit. J. Haemat.135:129,2006). As low urinary hepcidin levels were also found in patients with Myelodysplastic Syndrome (MDS), mainly in those with refractory anemia (RA) with or without ring sideroblasts (RARS) and iron overload, we set out to examine whether plasma factor(s) in MDS might also affect the expression of liver genes of iron metabolism. Patients and methods. Serum samples were collected from 19 MDS patients, average age: 75.7 y, Hb 6.5–12.0 gm/dl; type and #: RA 11, RARS 5 and 3 RA with excess of blasts (RAEB). The international prognostic score (IPSS) was low in 13/19 and intermediate 1 (Int 1) in 6/19. Only 7/19 patients received less that 5 blood units, while 12/19 received 20–140 units and in 11/19 serum ferritin was >1000 ng/ml. The serum samples were incubated with human hepatoma HepG2 cells, which were harvested and their RNA isolated and analyzed by quantitative RT-PCR for: hepcidin (Hamp), the lipocalin Ngal, HFE, transferrin receptors (TfR) 1 and 2, and DMT1-IRE(−). Values were normalized against those obtained from 3 healthy individuals. Results and discussion. An apparently normal expression of all the above genes was found in 13/19 patients (group I), whereas in the remaning 6/19 (group II) there was: A. a significant increase in expression relative to normal controls (1.0±0.20) of Ngal (4.64±2.15) p<0.01, TfR1 (5.24±0.59) p<0.01, HFE (1.76±0.12) p<0.05 and DMT1-IRE(−) (1.64±0.24) p<0.05; B. a significant decrease in TfR2 (0.19±0.11) p <0.01 and C. an increased Hamp expression in only 3/6 (7.2±5.0) p<0.05 patients and normal expression in 2/6 (1.03±0.3). No clear correlation could be established between expression of the above mentioned genes and iron overload parameters (serum iron and/or ferritin) or the number of transfusions. This study shows a heterogeneous behavior of MDS sera in eliciting gene expression and highlights that increased Hamp expression of HepG2 cells in response to plasma factors is found only in a small fraction of this class of iron overloaded patients. Thus as in thalassemia (1), most of the MDS sera with ferritin levels >1000 ng/ml failed to induce Hamp, suggesting that also in MDS patients there might be circulating factors overriding the serum iron effect on Hamp expression. It remains to be established whether the putative factors modulating expression of key genes of liver iron metabolism in MDS are of the same origin or biochemical character as in thalassemia.

Multiple Causes of Iron Overload In Tissues, Cells and Subcellular Compartments

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-27-SCI-27
Author(s):  
Tracey Rouault
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Cluster Assembly ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Iron

Abstract Abstract SCI-27 Iron metabolism is regulated in mammals to assure that adequate iron is delivered to the hematopoietic system to support erythropoiesis. In systemic iron metabolism, regulation of both iron uptake from the diet and release from erythrophagocytosing macrophages is coordinated by action of the peptide hormone, hepcidin, which inhibits activity of the iron exporter, ferroportin. In general, high expression of hepcidin diminishes duodenal iron uptake and reduces macrophage iron release, a combination observed in the anemia of chronic disease. Low expression of hepcidin, which is synthesized by hepatocytes and influenced by transferrin receptor 2, HFE, hemojuvelin and bone morphogenetic receptors, facilitates iron uptake. Mutations affecting genes in the hepcidin pathway cause hemochromatosis, characterized by systemic iron overload that affects mainly hepatocytes and cardiac myocytes, but spares the CNS. In contrast, there are several degenerative diseases of the CNS in which neuronal iron overload is prominent and may play a causal role. The underlying pathophysiologies of neuronal brain iron accumulation syndromes remain unclear, even though several causal genes have been identified, including pantothenate kinase 2 and aceruloplasminemia. In some cases, increased iron may be inaccessible, and cells may suffer from functional iron insufficiency, as we propose for animals that lack iron regulatory protein 2. It is also possible that errors in subcellular iron metabolism can lead to mitochondrial iron overload and concomitant cytosolic iron deficiency, a combination observed in Friedreich ataxia, ISCU myopathy, and the sideroblastic anemia caused by glutaredoxin 5 deficiency. In each of these diseases, mitochondrial iron-sulfur cluster assembly is impaired, and it appears that normal regulation of mitochondrial iron homeostasis depends on intact iron-sulfur cluster assembly. Finally, in heme oxygenase 1 deficient animals, macrophages in the spleen and liver die upon erythrophagocytosis, and failure to normally metabolize heme leads to shift of heme iron to proximal tubules and macrophages of the kidney. Thus, treatment of “iron overload” must depend on the underlying causes, and removal of iron is appropriate in hemochromatosis, but more specific forms of therapy are needed for other forms of iron overload. 1. Ye, H. & Rouault, T. A. (2010). Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry 49, 4945–4956. 2. Zhang, A. S. & Enns, C. A. (2009). Molecular mechanisms of normal iron homeostasis. Hematology Am Soc Hematol Educ Program 207–214. 3. Ye, H., Jeong, S. Y., Ghosh, M. C., Kovtunovych, G., Silvestri, L., Ortillo, D., Uchida, N., Tisdale, J., Camaschella, C. & Rouault, T. A. (2010). Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest 120, 1749–1761. 4. Ghosh, M. C., Tong, W. H., Zhang, D., Ollivierre-Wilson, H., Singh, A., Krishna, M. C., Mitchell, J. B. & Rouault, T. A. (2008). Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. Proc Natl Acad Sci U S A 105, 12028–12033. 5. Crooks, D. R., Ghosh, M. C., Haller, R. G., Tong, W. H. & Rouault, T. A. (2010). Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood 115, 860–869. Disclosures: No relevant conflicts of interest to declare.

Functional Validation and Clinical Significance Of a Newly Established Non-Transferrin-Bound Iron (NTBI) Assay System Utilizing Conventional Automated Analyzer

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 960-960
Author(s):  
Satoshi Ito ◽  
Katsuya Ikuta ◽  
Lynda Addo ◽  
Mayumi Hatayama ◽  
Yasumichi Toki ◽  
...  
Keyword(s):  
Iron Overload ◽  
Healthy Volunteers ◽  
Serum Ferritin ◽  
Iron Metabolism ◽  
Physiological Saline ◽  
The Body ◽  
Assay System ◽  
Positive Group ◽  
New Findings ◽  
Medical University

Abstract Introduction Iron is an essential metal in the body. However, iron overload is toxic, as excess ‘free’ reactive iron produces damaging free radicals which can lead to cellular and organ damage. Iron homeostasis is therefore tightly regulated. However, when iron balance collapses (as in prolonged transfusion), transferrin (Tf) becomes fully saturated and non-Tf-bound iron (NTBI) appears in serum. NTBI levels are increased in various iron overload states, and decreased after treatment with iron chelators (example deferasirox) in thalassemia and hemochromatosis, and is therefore important in evaluating and monitoring iron toxicity risks. Although several NTBI measurement methods have been reported, they are extremely complicated and low in sensitivity, thus very few laboratories can quantify NTBI. Consequently, NTBI research has not progressed significantly to date. We previously established a novel assay system utilizing automated analyzers (used widely in clinical laboratories for diagnostic testing), which we presented at ASH 2012 poster session. Using this assay, we sought to measure NTBI in iron overloaded animals, healthy volunteers and patients’ sera. Methods Data was analyzed using the HITACHI 7700 auto analyzer. Human serum was obtained from 41 healthy volunteers (16 males, 25 females) and 118 patients (61 males, 57 females) receiving treatment at the Asahikawa Medical University Hospital. Average age of healthy volunteers was 34.4 years and 60.6 years in patients. The primary diagnosis in patients included malignant lymphoma, acute myeloid leukemia, myelodysplastic syndromes, multiple myeloma and others. Patient data, including hemoglobin, biochemical markers including C-reactive protein (CRP), serum iron (sFe), unsaturated iron binding capacity (UIBC) and serum ferritin were obtained from the patients’ records or determined for the healthy volunteers. Mice were administered intraperitoneal injections of physiological saline solution or iron-dextran (Fe 1 mg/day or Fe 10 mg/day) for 5 days, after which serum was collected. Rats received intravenous injections of physiological saline or iron sucrose. Serum was collected after 1, 3 and 6 hours iron injection. Informed consent was obtained from all study subjects, and study protocol and experimental procedures were approved by the Ethical and Animal Experiments Committee of Asahikawa Medical University and Hospital. Statistical analysis was done using Mann-Whitney U-test and Student paired t-test. Results and Conclusion Median NTBI in healthy volunteers was 0.45 μM; no statistical difference was found between the sexes. Median NTBI in the patient group was 0.38 mM, a slight decrease to that of the healthy volunteers (statistical significance p=0.0144). In transferin saturation (TSAT) and NTBI measurement in the patients, NTBI increased markedly as TSAT reached over 80%. A slightly positive correlation was found between sFe and NTBI, but no significant correlation was observed between serum ferritin and NTBI. CRP>0.3 mg/dL is a positive indicator of inflammation, so median NTBI was compared with CRP-positive and -negative groups; NTBI decreased significantly in the CRP-positive group (p<0.05). On the other hand, median serum ferritin significantly increased in the CRP-positive group (p<0.05). This data shows NTBI is an unmistakably unique marker of iron metabolism unlike serum ferritin. This characteristic of NTBI may be helpful in overcoming problems with serum ferritin use as a marker of iron metabolism (serum ferritin is affected by inflammation), and provide additional information that directly reflects changes in iron metabolism, even in inflammatory states. Compared to the control group, a statistically significant increase in NTBI was observed in the Fe 10 mg/day mice group. After intravenous iron administration in the rats, NTBI was 0.16±0.04 μM at pre-treatment, and rapidly increased to 2.78±0.62 μM after 1 hour iron injection; this increase decreased over time, indicating that NTBI can be used not only as a marker to evaluate iron overload but also to precisely monitor dynamic changes in iron in serum. Our novel system revealed new findings and it indicates that this system must be useful for studying the physiological and clinical importance of NTBI. Disclosures: No relevant conflicts of interest to declare.

Iron Metabolism before Allo-HSCT in Patients with Acute Leukemia and Impact of Iron Overload on Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2461-2461
Author(s):  
Jimin Shi ◽  
Xuying Pei ◽  
Yi Luo ◽  
Yamin Tan ◽  
Yanmin Zhao ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Bacterial Infections ◽  
Conflicts Of Interest ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Increased Risk

Abstract Objective: Iron overload is common in patients with acute leukemia who undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT). We performed a comprehensive analysis of iron parameters to assess these patients' iron metabolism, and studied the prognostic impact of pretransplant iron overload on the outcome of transplantation. Methods: In this retrospective study, we studied 124 patients undergoing myeloablative allo-HSCT between 2012 and 2014. Serum iron (SI), serum ferritin (SF), hepcidin (Hepc) and soluble transferrin receptor (sTfR) were measured before transplant. We analyzed the effect of elevated pretransplant ferritin on acute graft versus host disease (aGVHD), infectious complications, overall survival (OS) and non-relapse mortality (NRM). Results: Date of 124 patients (including 56 cases of acute lymphocytic leukemia and 68 cases of acute myeloid leukemia) were analyzed. Median SI, SF, Hepc and sTfR values were 12.15 umol/L, 667.05 ng/ml, 369.50 ng/L and 7.69 ng/ml, respectively. Iron overload (defined as SF>1000 ng/ml) were observed in 27.42% of patients. Pretransplant iron overload was significantly associated with increased risk of bacterial infections during the early post-transplant period, and with reduced risk of aGVHD. Pretransplant iron overload increased NRM and reduced OS, but there were no significant differences. Conclusion: Patients with acute leukemia regularly develop iron overload before they undergoing allo-HSCT. Pretransplant iron overload was correlated with transplantation outcome. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document