Functional Iron Deficiency Research Articles

Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells.

Neurons require iron to support their metabolism, growth, and differentiation, but are also susceptible to iron-induced oxidative stress and cytotoxicity. Ferritin, a cytosolic iron storage unit, mediates cellular adaptation to fluctuations in iron delivery. NCOA4 has been characterized as a selective autophagic cargo receptor facilitating the mobilization of intracellular iron from ferritin. This process named ferritinophagy results in the degradation of ferritin and the consequent release of iron into the cytosol. Here we demonstrate that NCOA4 is important for the adaptation of the HT22 mouse hippocampal neuronal cell line to cellular iron restriction. Additionally, we determined the pathophysiological implications of impaired ferritinophagy via functional analysis of the omics profile of HT22 cells deficient in NCOA4. NCOA4 silencing impaired ferritin turnover and was cytotoxic when cells were restricted of iron. Quantitative proteomics identified IRP2 accumulation among the most prominent protein responses produced by NCOA4 depletion in HT22 cells, which is indicative of functional iron deficiency. Additionally, proteins of apoptotic signaling pathway were enriched by those responsive to NCOA4 deficiency. Transcriptome profiles of NCOA4 depletion revealed neuronal cell death, differentiation of neurons, and development of neurons as potential diseases and bio functions affected by impaired ferritinophagy, particularly, when iron was restricted. These findings identify an integral role of NCOA4-mediated ferritinophagy in the maintenance of iron homeostasis by HT22 cells, and its potential implications in controlling genetic pathways of neurodevelopment and neurodegenerative diseases.

Alleviation of functional iron deficiency by SGLT2 inhibition in patients with type 2 diabetes.

Alleviation of functional iron deficiency by SGLT2 inhibition in patients with type 2 diabetes.

Role of Iron Deficiency in Heart Failure-Clinical and Treatment Approach: An Overview.

The association of chronic heart failure (CHF) and iron deficiency (ID) with or without anemia is frequently encountered in current medical practice and has a negative prognostic impact, worsening patients' exercise capacity and increasing hospitalization costs. Moreover, anemia is common in patients with chronic kidney disease (CKD) and CHF, an association known as cardio-renal anemia syndrome (CRAS) possessing a significantly increased risk of death. This review aims to provide an illustrative survey on the impact of ID in CHF patients-based on physiopathological traits, clinical features, and the correlation between functional and absolute ID with CHF-and the benefit of iron supplementation in CHF. We selected the most recent publications with important scientific content covering the association of CHF and ID with or without anemia. An intricate physiopathological interplay is described in these patients-decrease in erythropoietin levels, activation of the renin-angiotensin-aldosterone system, systemic inflammation, and increases in hepcidin levels. These mechanisms amplify anemia, CHF, and CKD severity and worsen patients' outcomes. Anemia is frequently encountered in CHF and represents a negative prognostic factor. Data from randomized controlled trials have underlined the administration of intravenous iron therapy (ferric carboxymaltose) as the only viable treatment option, with beneficial effects on quality of life and exercise capacity in patients with ID and systolic heart failure.

Characteristics of anemia in heart failure: iron metabolism, erythropoietic activity and markers of inflammation

Aim. To determine the characteristics of erythrocyte parameters, iron metabolism, erythropoiesis, inflammation markers in patients with heart failure (CHF) and anemia.Material and methods. The study included 68 patients with HF to describe the characteristics of anemia (general group). Patients of the general group were divided into 3 subgroups depending on the serum ferritin (SF) and transferrin saturation (TS).Results. Anemia in HF is not always associated with iron deficiency (ID), characterized by inadequate production of erythropoietin, increased levels of C-reactive protein and hepcidin. From the general group of patients, the following were distinguished: absolute ID (43%), functional ID (19%), and non-ID anemia (38%).Conclusion. In the general group of patients with HF, anemia is normochromic, normocytic, characterized by high levels of C-reactive protein, hepcidin, and inadequate production of erythropoietin. Patients with absolute and functional ID do not differ in the main iron metabolism parameters and in general account for 62% (p=0,01). In these two subgroups, iron supplements should be prescribed at further stages.

ВЛИЯНИЕ РОСТА СКЕЛЕТНО-МЫШЕЧНОЙ МАССЫ НА ПОКАЗАТЕЛИ ОБМЕНА ЖЕЛЕЗА У ВОЕННОСЛУЖАЩИХ ПО ПРИЗЫВУ В ПЕРИОД АДАПТАЦИИ К УСЛОВИЯМ ВОЕННОЙ СЛУЖБЫ

Thousands of young men are conscripted for military service with various nutritional status and physical fitness condition every year. The adaptation of conscripted soldiers to the factors of military service occurs at three levels: physiological, psychological and social. The purpose of the study was to assess the dynamic changes of body structure parameters in conscripted soldiers during 6 months of service by conscription and to determine the effect of skeletal muscle mass growth on iron metabolism during adaptation to military service conditions. A prospective observational study involved 145 conscripted soldiers from one of the military units after informed consent. The study was performed from the moment of conscription for military service in 3 stages with an interval of 3 months using a four-component model of body structure and a four-component model of iron metabolism. The skeletal muscle mass and adipose tissue mass and were determined caliperometrically. Hematological and biochemical parameters of iron metabolism were assessed. Dynamic changes and types of growth of the skeletal muscle mass, as well as changes in the parameters of iron metabolism have been obtained. The body weight of conscripted soldiers changes slightly within 6 months from the moment of conscription. At the same time internal changes occurred in the structure of the body of conscripted soldiers due to an increase in skeletal muscle mass and a decrease in the mass of adipose tissues. The types of skeletal muscle mass growth were determined among conscripted soldiers. There were an increase in skeletal muscle mass and hemoglobin fund to provide them oxygen by the influence of increased physical loading. It led to a decrease in iron stores, estimated by serum ferritin, and signs became more pronounced of iron deficiency erythropoiesis, which were determined in erythrocyte indexes. These combined changes can be assessed as functional iron deficiency or iron deficiency without anemia.

Prevalence of Iron Deficiency in Chronic Heart Failure Patients in a Tertiary Care Hospital: An Observational Study

Introduction: This is an observational study to explorethe prevalence of irondeficiency (ID) and the relationshipbetween the severity of chronic heart failure (CHF) and the degree of ID in CHF patients.Objective: The objective of the study was to assess the extent of ID and its adverse effects on patients with CHF.This study was intended to assess the prevalence and effect of ID in anaemic as well as, non-anaemic subjects.Methodology: Study subjects were from OPDs and IPD patients with the diagnosis of CHF, based on clinical and2D echo findings. ID was diagnosed by basing on iron profile along with transferin saturation (TSAT). The studyperiod was from January 2017 to March 2018; from which 109 patients were included. In those cases, trans-thoracicechocardiography, chest X-Ray, necessary blood biochemistry and CBC were done. Data collected on 109 cases ofCHF were analyzed using IBM SPSS 24.0 software.Results: Iron deficiency was present in 86.2% of patients, 40.3% had functional ID (ferritin 100-300 and TSATless than 20%) and 45.9% had absolute ID (ferritin less than 100). Interestingly, out of those who had no anaemiaclinically or laboratory report wise approximately one-fourth of the patients had iron deficiency.Conclusion: This study reveals that ID in HF is a hugely ignored area in India. This study brings out the need forlarge-scale studies in India so that this easily treatable condition can be well characterized and routine testing forID could be introduced in the guidelines of our country.

Improved Diagnosis of Iron Deficiency Anemia in the Critically Ill via Fluorescence Flowcytometric Hemoglobin Biomarkers

Iron deficiency anemia (IDA) is common in critically ill patients treated in the intensive care unit (ICU), and it can lead to severe consequences. Precise and immediate diagnostics are not available, but they are inevitably needed to administer adequate therapy. Serological parameters such as serum ferritin and transferrin saturation (TSAT) are heavily influenced by simultaneous inflammation reactions, resulting in the need for more suitable parameters. Reticulocyte biomarkers such as reticulocyte hemoglobin content (RET-He) and Delta-hemoglobin equivalent (Delta-He) determined by fluorescence flowcytometry are more specific for the diagnosis of IDA-based anemia and should be investigated for this purpose. In a prospective cohort single-center study, serum ferritin and transferrin saturation (TSAT) were collected and compared to RET-He and Delta-He by performing a receiver operating curve (ROC) analysis. The sensitivity and specificity of a single variable or the combination of two variables, as well as cutoff values, for the diagnosis of IDA were calculated. A group comparison for IDA patients without IDA was performed for a control group. A total of 314 patients were enrolled from an interdisciplinary ICU. RET-He (area under the curve (AUC) 0.847) and Delta-He (AUC 0.807) did indicate iron-deficient anemia that was more specific and sensitive in comparison to serum ferritin (AUC 0.678) and TSAT (AUC 0.754). The detection of functional iron deficiency (FID) occurred in 28.3% of cases with anemia. Determination of RET-He and Delta-He allows for the increased precision and sensitivity of iron-deficient anemia in the ICU.

Prognostic Value of Serum Transferrin Analysis in Patients with Ovarian Cancer and Cancer-Related Functional Iron Deficiency: A Retrospective Case-Control Study.

(1) Background: There are no reliable and widely available markers of functional iron deficiency (FID) in cancer. The aim of the study was to evaluate the role of transferrin (Tf) as a marker of cancer of the ovary (CrO) and related FID. (2) Methods: The study groups consisted of 118 patients with CrO and 69 control females. Blood serum iron status was determined on a Beckman Coulter AU (USA) analyzer. Tf quantification was performed by immunoturbidimetry. The relative contents of apo- and holo-Tf (iron-free and iron-saturated Tf, respectively) were determined in eight patients and a control female by immunochromatographic analysis based on the use of monoclonal single-domain antibodies (nanobodies). (3) Results: Four groups of patients with different iron statuses were selected according to ferritin and transferrin saturation values: absolute iron deficiency (AID) (n = 42), FID (n = 70), iron overload (n = 4), normal iron status (n = 2). The groups differed significantly in Tf values (p < 0.0001). Lower values of Tf were associated with FID. Furthermore, FID is already found in the initial stages of CrO (26%). Immunosorbents based on nanobodies revealed the accumulation of apo-Tf and the decrease in holo-Tf in patients with CrO. (4) Conclusions: Tf may be a promising tool for diagnosing both CrO and associated FID.

The association between iron deficiency and outcomes: a secondary analysis of the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial.

In the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial, the use of intravenous iron did not reduce the need for blood transfusion or reduce patient complications or length of hospital stay. As part of the trial protocol, serum was collected at randomisation and on the day of surgery. These samples were analysed in a central laboratory for markers of iron deficiency. We performed a secondary analysis to explore the potential interactions between pre-operative markers of iron deficiency and intervention status on the trial outcome measures. Absolute iron deficiency was defined as ferritin <30μg.l-1 ; functional iron deficiency as ferritin 30-100μg.l-1 or transferrin saturation < 20%; and the remainder as non-iron deficient. Interactions were estimated using generalised linear models that included different subgroup indicators of baseline iron status. Co-primary endpoints were blood transfusion or death and number of blood transfusions, from randomisation to 30 days postoperatively. Secondary endpoints included peri-operative change in haemoglobin, postoperative complications and length of hospital stay. Most patients had iron deficiency (369/452 [82%]) at randomisation; one-third had absolute iron deficiency (144/452 [32%]) and half had functional iron deficiency (225/452 [50%]). The change in pre-operative haemoglobin with intravenous iron compared with placebo was greatest in patients with absolute iron deficiency, mean difference 8.9g.l-1 , 95%CI 5.3-12.5; moderate in functional iron deficiency, mean difference 2.8g.l-1 , 95%CI -0.1 to 5.7; and with little change seen in those patients who were non-iron deficient. Subgroup analyses did not suggest that intravenous iron compared with placebo reduced the likelihood of death or blood transfusion at 30 days differentially across subgroups according to baseline ferritin (p=0.33 for interaction), transferrin saturation (p=0.13) or in combination (p=0.45), or for the number of blood transfusions (p=0.06, 0.29, and 0.39, respectively). There was no beneficial effect of the use of intravenous iron compared with placebo, regardless of the metrics to diagnose iron deficiency, on postoperative complications or length of hospital stay.

Anemia on Chronic Kidney Disease: The Role of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

Anemia is one of the homeostatic abnormalities caused by chronic kidney disease and also frequently problem encountered in end-stage renal disease patients, regardless of the hemodialysis treatment. Anemia in chronic kidney disease significantly impairs kidney function, increases morbidity and mortality risk, and deteriorates the quality of life. Chronic kidney disease’s patients with anemia conditions are affected by numerous factors, including decreased production of endogenous erythropoietin, functional and absolute iron deficiency, and elevated hepcidin levels due to inflammation, particularly in hemodialysis patients. Treatment options for anemia in chronic kidney disease include exogenous erythropoietin and iron supplementation. A new mechanism known as the "hypoxia-sensing system" termed a mediator of erythropoietin synthesis, has been proposed to boost endogenous erythropoietin synthesis. The hypoxia-inducible factor activates specific gene expression and contributes to a physiological response to lower tissue oxygen levels. Chronic kidney disease’s patients who are contraindicated or are hyporesponsive to therapy with erythropoiesis-stimulating drugs may utilize this mechanism as an alternative.

Dysregulation of iron metabolism modulators in virologically suppressed HIV-infected patients.

Iron metabolism plays an essential role in cellular functions. Since virologically suppressed chronic HIV-infected subjects under effective antiretroviral treatment (ART) exhibit a persistent immune dysfunction that leads to comorbidities, iron homeostasis may be relevant in this context. We aimed to explore iron metabolism in virologically suppressed chronic HIV infected subjects under a successful ART. In this retrospective study, traditional iron metabolism biomarkers (total iron, ferritin, transferrin, and transferrin saturation index), as well as soluble transferrin receptor (sTfR), hepcidin, and inflammatory markers were determined in virologically suppressed chronic HIV-infected subjects under at least 2 years of ART (HIV) who also had >350 CD4-T-cells/mm3 (N=92) from Spain. As controls, we collected non-HIV age-matched healthy donors (Young, N=25) and elderly subjects (>65 years old; Elderly; N=25). Additionally, an external group of non-HIV patients with ferritin<50 ng/mL diagnosed with absolute iron deficiency (Ferropenic group; N=84) was included. Comparisons between groups were performed using Kruskal-Wallis or Mann-Whitney U-tests, while associations between variables were explored by Spearman's rho correlation coefficient. We selected samples from HIV-infected subjects (aged 42[34-47], 95% males), young age-matched (aged 40[30-58], 60% males), and elderly controls (aged 82[78-88], 100% males). Compared to both healthy (Young and Elderly) groups, HIV exhibited decreased iron, transferrin saturation, and sTfR, and increased ferritin, but similar hepcidin levels. Notably, associations between sTfR and iron (Young, r=-0.587, p=0.002; Elderly, r=-0.496, p=0.012) or transferrin saturation index (Young, r=-0.581, p=0.002; Elderly, r=-0.489, p=0.013) were negative in both controls while positive in HIV (r=0.464, p<0.0001 and r=0.421, p<0.0001, respectively). Moreover, the expected negative correlation between hepcidin and sTfR, observed in controls (Young, r=-0.533, p=0.006; Elderly, r=-0.473, p=0.017), was absent in HIV (r=0.082; p=0.438). Interestingly, the HIV inflammatory profile differed from the Elderly one, who despite their inflammaging-related profile, succeed in maintaining these associations. Furthermore, subjects from the ferropenic group (aged 42[32-51], 5% males), showing significantly lower levels of hepcidin and higher sTfR, as expected, reflected similar correlations as those Young and Elderly, in contrast to HIV. Virologically suppressed chronic HIV-infected patients under successful ART exhibit altered levels of iron metabolism modulators suggesting a complex functional iron deficiency.

Prise en charge de la carence martiale au cours de la maladie rénale chronique : mise au point et proposition d’un algorithme

Iron deficiency is very common in chronic kidney disease, even before the dialysis stage. It is an independent factor of morbidity and mortality in patients with non-dialysis chronic kidney disease. During chronic kidney disease, iron deficiency is defined by a transferrin saturation <20% and/or a serum ferritin <100 μg/L. In France, about half of non-dialysis chronic kidney disease patients have absolute iron deficiency (transferrin saturation <20% and serum ferritin <100 μg/L) and/or functional iron deficiency (transferrin saturation <20% and serum ferritin >100 μg/L). Despite this, iron deficiency is usually not investigated. In fact, more than 60% of nephrologists do not assess iron status at least once a year. In addition, iron deficiency is rarely treated: only 12% of patients are prescribed oral or intravenous iron. Early detection and treatment are fundamental and should be systematic. In order to help improve the management of iron deficiency among non-dialysis chronic kidney disease patients, we propose an algorithm that takes into account current recommendations and the most recent data from the literature. Initial blood test requires the measurement of hemoglobin concentration, transferrin saturation and serum ferritin. A transferrin saturation <20% establishes the diagnosis of iron deficiency and the serum ferritin level points towards an absolute or functional deficiency. The combination of both values makes it possible to adapt the treatment, particularly in an inflammatory context where oral iron is not effective.

Pleotropic effects of hypoxia-inducible factor-prolyl hydroxylase domain inhibitors: are they clinically relevant?

Anemia is common in patients with chronic kidney disease (CKD) and is mainly caused by insufficient production of erythropoietin from fibrotic kidney. Because anemia impairs quality of life and overall prognosis, recombinant human erythropoietin-related products (erythropoiesis-stimulating agents, ESAs) have been developed to increase hemoglobin level for decades. However, many safety concerns have been announced regarding the use of ESAs, including an increased occurrence of cardiovascular events, vascular access thrombosis, cancer progression, and recurrence. Hypoxia-inducible factor (HIF) is crucial to erythropoietin production, as a result, prolyl hydroxylase domain (PHD) enzyme inhibitors have been new therapeutic agents for the treatment of anemia in CKD. They can be administered orally, which is a preferred route for patients not undergoing hemodialysis. In clinical trials, PHD inhibitor could induce noninferior effect on erythropoiesis and improve functional iron deficiency compared with ESAs. Although no serious adverse events were reported, safety is still a concern because HIF stabilization induced by PHD inhibitor has pleotropic effects, such as angiogenesis, metabolic change, and cell survival, which might lead to unwanted deleterious effects, including fibrosis, inflammation, cardiovascular risk, and tumor growth. More molecular mechanisms of PHD inhibition and long-term clinical trials are needed to observe these pleotropic effects for the confirmation of safety and efficacy of PHD inhibitors.

Management of anaemia in French dialysis patients: results from a large epidemiological retrospective study.

Limited real-world data are available in Europe, especially France, regarding the therapeutic management of anaemia in patients with dialysis-dependent chronic kidney disease (DD CKD). This retrospective, longitudinal, observational study was based on medical records from the MEDIAL database of not-for-profit dialysis units in France. From January to December 2016, we included eligible patients (≥18 years), with a diagnosis of CKD and receiving maintenance dialysis. Patients with anaemia were followed up for 2 years after inclusion. Patient demographic data, anaemia status, CKD-related anaemia treatments, and treatment outcomes including laboratory test results were evaluated. Of 1632 DD CKD patients identified from the MEDIAL database, 1286 had anaemia; 98.2% of patients with anaemia were receiving haemodialysis at index date (ID). Of patients with anaemia, 29.9% had haemoglobin (Hb) levels of 10-11g/dL and 36.2% had levels of 11-12g/dL at ID. Furthermore, 21.3% had functional iron deficiency and 11.7% had absolute iron deficiency. The most commonly prescribed treatments at ID for patients with DD CKD-related anaemia were intravenous (IV) iron with erythropoietin-stimulating agents (ESAs) (65.1%). Among patients initiating ESA treatment at ID or during follow-up, 347 (95.3%) reached the Hb target of 10-13g/dL and maintained response within the target Hb range for a median duration of 113 days. Despite combined use of ESAs and IV iron, duration within the Hb target range was short, suggesting that anaemia management can be further improved.

Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors.

Chronic kidney disease (CKD) affects approximately 10% of the worldwide population; anaemia is a frequent complication. Inadequate erythropoietin production and absolute or functional iron deficiency are the major causes. Accordingly, the current treatment is based on iron and erythropoiesis stimulating agents (ESAs). Available therapy has dramatically improved the management of anaemia and the quality of life. However, safety concerns were raised over ESA use, especially when aiming to reach near-to-normal haemoglobin levels with high doses. Moreover, many patients show hypo-responsiveness to ESA. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors (HIF-PHIs) were developed for the oral treatment of anaemia in CKD to overcome these concerns. They simulate the body's exposure to moderate hypoxia, stimulating the production of endogenous erythropoietin. Some molecules are already approved for clinical use in some countries. Data from clinical trials showed non-inferiority in anaemia correction compared to ESA or superiority for placebo. Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors may also have additional advantages in inflamed patients, improving iron utilisation and mobilisation and decreasing LDL-cholesterol. Overall, non-inferiority was also shown in major cardiovascular events, except for one molecule in the non-dialysis population. This was an unexpected finding, considering the lower erythropoietin levels reached using these drugs due to their peculiar mechanism of action. More data and longer follow-ups are necessary to better clarifying safety issues and further investigate the variety of pathways activated by HIF, which could have either positive or negative effects and could differentiate HIF-PHIs from ESAs.

A protocol for a prospective, multicentre observational study to determine if nonanaemic iron deficiency worsens postoperative outcome in patients undergoing elective surgery for resection of colorectal cancer: The NATO study.

Preoperative absolute and functional iron deficiency anaemia is associated with poor postoperative outcomes in patients undergoing surgery for colorectal cancer. It is biologically plausible that "early", or "nonanaemic" iron deficiency may also be associated with worse postoperative outcomes in similar cohorts, albeit at lesser severity than that seen for anaemia. The evidence supporting this assertion is of low quality. We have designed a prospective, observational study to delineate associations between preoperative non-anaemic iron deficiency and postoperative outcomes after surgery for colorectal cancer. Patients without anaemia, undergoing elective surgery for colorectal cancer will be allocated to an iron replete or an iron deficient group based on preoperative transferrin saturation. The primary outcome is days alive and at home on postoperative day 90. Secondary outcomes include days alive and at home on postoperative day 30, length of hospital stay, readmission to acute care, postoperative complications, health-related quality of life scores, quality of postoperative recovery, and requirement for allogeneic blood transfusion. The planned sample size is 422 patients, which has 80% power to detect a two-day difference in the primary outcome. The study commenced in May 2019. The results of this study will provide patients and clinicians with high-quality evidence concerning associations between nonanaemic iron deficiency and patient-centred outcomes after surgery for colorectal cancer. The study will be conducted in multiple urban and rural centres across Australia and New Zealand. The results will be highly generalisable to contemporary surgical practice and should be rapidly translated.

Functional iron status of chronic kidney disease patients at the University of Ilorin Teaching Hospital, Ilorin, Nigeria.

Functional iron deficiency has been found to be a common cause of poor response to erythropoiesis stimulating agents in anaemic patients with chronic kidney disease (CKD). Assess the functional iron status of patients with chronic kidney disease. This was a hospital based cross sectional study. The study subjects were chronic kidney disease patients with age and sex matched healthy controls. Full blood count, serum ferritin, soluble transferring receptor, C-reactive protein, serum iron and total iron binding capacity were measured in the patients and healthy controls.Data was analyzed with statistical package for the social sciences software version 22.0. And the level of statistical significance was set at p. value < 0.05. The mean ± SD of the age of patient with CKD was 55.0 + 15.4 years, while that of controls was 52.7 + 13.6 years. The mean serum ferritin, serum iron, TIBC and CRP were significantly higher in patients compared with controls (p<0.001, 0.023, <0.001 and 0.001) respectively. Functional iron deficiency was seen in 19.5% of patients with CKD. The predominant form of iron deficiency in our study was functional iron deficiency.

Genetic regulation of iron homeostasis in sideropenic patients with mild COVID-19 disease under a new oral iron formulation: Lessons from a different perspective

BackgroundSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) needs iron to replicate itself. Coronaviruses are able to upregulate Chop/Gadd153 and Arg1 genes, consequently leading to CD8 lymphocytes decrease, degradation of asparagine and decreased nitric oxide (NO), thus impairing immune response and antithrombotic functions. Little is known about regulation of genes involved in iron metabolism in paucisymptomatic patients with COVID-19 disease or in patients with iron deficiency treated with sucrosomial iron. MethodsWhole blood was taken from the COVID-19 patients and from patients with sideropenic anemia, treated or not (control group) with iron supplementations. Enrolled patients were: affected by COVID19 under sucrosomal iron support (group A), affected by COVID-19 not under oral iron support (group B), iron deficiency not under treatment, not affected by COVID19 (control group). After RNA extraction and complementary DNA (cDNA) synthesis of Arg1, Hepcidin and Chop/Gadd153, gene expression from the 3 groups was measured by qRT-PCR. M2 macrophages were detected by cytofluorimetry using CD163 and CD14 markers. ResultsForty patients with COVID-19 (group A), 20 patients with iron deficiency treated with sucrosomial iron (group B) and 20 patients with iron deficiency not under treatment (control group) were enrolled. In all the patients supported with oral sucrosomial iron, the gene expression of Chop, Arg1 and Hepcidin genes was lower than in sideropenic patients not supported with iron, M1 macrophages polarization and functional iron deficiency was also lower in group A and B, than observed in the control group. ConclusionsNew oral iron formulations, as sucrosomial iron, are able to influence the expression of genes like Chop and Arg1 and to influence M2 macrophage polarization mainly in the early phase of COVID-19 disease.

Anemia and iron in internal medicine: an Italian survey and a review on iron intravenous therapy in medical patients

In Italy, Internal Medicine Units hospitalize approximately 1,300,000 patients, often elderly and comorbid. The prevalent diagnoses are respiratory diseases, heart failure, or pneumonia. As a matter of fact, anemia is probably underestimated in the compilation of the official discharge forms (SDO) according to ICD-9 diagnostic codes. We promoted a survey among the Members the Italian Scientific Society of Internal Medicine (FADOI) with the aim to investigate the prevalence of anemia and iron deficiency, over than certain aspects related to the therapeutic management of patients with anemia. Furthermore, we performed a review summarizing current evidence for iron intravenous therapy in these patients. According to the survey, anemia is present in around half of the patients hospitalized in Internal Medicine, and about a quarter of them shows iron metabolism alterations. In the evaluation of iron metabolism, the dosage of ferritin is the most requested exam, whereas transferrin saturation is less considered. By focusing on some categories of patients, the awareness of the usefulness of intravenous iron therapy in patients with heart failure seems to be sufficiently common (76% of physicians), while it seems lower (60%) in the management of patients with chronic kidney disease (CKD) and anemia. Finally, more than 75% of the physicians answered that, in their hospital, there are few outpatients’ offices or diagnostic pathways dedicated to patients with anemia. Anemia due to absolute or functional iron deficiency is particularly prevalent in Internal Medicine inpatients. For this reason, an accurate evaluation of iron profile and an adequate iron therapy is mandatory in these patients. Recent studies show that, in patients with heart failure, intravenous iron therapy is an effective way of improving patients’ health, regardless of the presence of anemia. Similarly, iron therapy results fundamental to optimize erythropoiesis-stimulating agent efficacy in patients with chronic renal failure. In the next future, other therapeutic aspects of intravenous iron therapy will be probably clarified by several interesting ongoing studies focused on these patients.

Lactate Production can Function to Increase Human Epithelial Cell Iron Concentration.

Under conditions of limited iron availability, plants and microbes have evolved mechanisms to acquire iron. For example, metal deficiency stimulates reprogramming of carbon metabolism, increasing activity of enzymes involved in the Krebs cycle and the glycolytic pathway. Resultant carboxylates/hydroxycarboxylates then function as ligands to complex iron and facilitate solubilization and uptake, reversing the metal deficiency. Similarly, human intestinal epithelial cells may produce lactate, a hydroxycarboxylate, during absolute and functional iron deficiency to import metal to reverse limited availability. Here we investigate (1) if lactate can increase cell metal import of epithelial cells in vitro, (2) if lactate dehydrogenase (LDH) activity in and lactate production by epithelial cells correspond to metal availability, and (3) if blood concentrations of LDH in a human cohort correlate with indices of iron homeostasis. Results show that exposures of human epithelial cells, Caco-2, to both sodium lactate and ferric ammonium citrate (FAC) increase metal import relative to FAC alone. Similarly, fumaric, isocitric, malic, and succinic acid coincubation with FAC increase iron import relative to FAC alone. Increased iron import following exposures to sodium lactate and FAC elevated both ferritin and metal associated with mitochondria. LDH did not change after exposure to deferoxamine but decreased with 24 h exposure to FAC. Lactate levels revealed decreased levels with FAC incubation. Review of the National Health and Nutrition Examination Survey demonstrated significant negative relationships between LDH concentrations and serum iron in human cohorts. Therefore, we conclude that iron import in human epithelial cells can involve lactate, LDH activity can reflect the availability of this metal, and blood LDH concentrations can correlate with indices of iron homeostasis.