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Hyperferritinemia in critically ill COVID-19 patients - Is ferritin the product of inflammation or a pathogenic mediator?
Gómez-Pastora, J, Weigand, M, Kim, J, Wu, X, Strayer, J, Palmer, AF, Zborowski, M, Yazer, M, Chalmers, JJ
Clinica chimica acta; international journal of clinical chemistry. 2020;:249-251
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2.
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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Iron in the General Population and Specificities in Older Adults: Metabolism, Causes and Consequences of Decrease or Overload, and Biological Assessment.
Manckoundia, P, Konaté, A, Hacquin, A, Nuss, V, Mihai, AM, Vovelle, J, Dipanda, M, Putot, S, Barben, J, Putot, A
Clinical interventions in aging. 2020;:1927-1938
Abstract
Iron is involved in many types of metabolism, including oxygen transport in hemoglobin. Iron deficiency (ID), ie a decrease in circulating iron, can have severe consequences. We provide an update on iron metabolism and ID, highlighting the particularities in older adults (OAs). There are three iron compartments in the human body: 1) the functional compartment, which consists of heme proteins including hemoglobin, myoglobin and respiratory enzymes; 2) iron reserves (IR), which consist mainly of liver stocks and are stored as ferritin; and 3) transferrin. There are two types of ID. Absolute ID is characterized by a decrease in IR. Its main pathophysiological mechanism is bleeding, which is often digestive and can be due to neoplasia, frequent in OAs. Biological assessment shows low serum ferritin and transferrin saturation (TS) levels. Furthermore, hypochromic microcytic anemia is frequent, and the serum-soluble transferrin receptor (sTfR) level is high. Functional ID, in which IR are high or normal, is due to inflammation, which is also frequent in OAs, particularly in its chronic form. Biological assessments show high serum ferritin, normal or low TS, and normal sTfR levels. Moreover, C-reactive protein is elevated, and there is moderate non-regenerative non-macrocytic anemia. The main characteristics of iron metabolism anomalies in the elderly are the high frequency of ID (20% of ID with anemia in adults ≥85 years) and the severity of its consequences, which include cognitive impairment in case of ID or iron overload and decrease of physical activity in case of ID. In conclusion, causes of ID are frequently intertwined in OAs as a result of the polymorbidity that characterizes them. ID can have dramatic consequences, especially in frail OAs. Thus, measuring the appropriate biological markers prevents errors in the positive diagnosis of ID type, clarifies etiology, and informs treatment-related decision-making.
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COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy.
Perricone, C, Bartoloni, E, Bursi, R, Cafaro, G, Guidelli, GM, Shoenfeld, Y, Gerli, R
Immunologic research. 2020;(4):213-224
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Abstract
SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still's disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.
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Iron deficiency among blood donors: experience from the Danish Blood Donor Study and from the Copenhagen ferritin monitoring scheme.
Rigas, AS, Pedersen, OB, Magnussen, K, Erikstrup, C, Ullum, H
Transfusion medicine (Oxford, England). 2019;:23-27
Abstract
Blood components collected from blood donors are an invaluable part of modern-day medicine. A healthy blood donor population is therefore of paramount importance. The results from the Danish Blood Donor Study (DBDS) indicate that gender, number of previous donations, time since last donation and menopausal status are the strongest predictors of iron deficiency. Only little information on the health effects of iron deficiency in blood donors exits. Possibly, after a standard full blood donation, a temporarily reduced physical performance for women is observed. However, iron deficiency among blood donors is not reflected in a reduced self-perceived mental and physical health. In general, the high proportion of iron-deficient donors can be alleviated either by extending the inter-donation intervals or by guided iron supplementation. The experience from Copenhagen, the Capital Region of Denmark, is that routine ferritin measurements and iron supplementation are feasible and effective ways of reducing the proportion of donors with low haemoglobin levels.
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Hyperferritinaemia: An Iron Sword of Autoimmunity.
Giemza-Stokłosa, J, Islam, MA, Kotyla, PJ
Current pharmaceutical design. 2019;(27):2909-2918
Abstract
BACKGROUND Ferritin is a molecule that plays many roles being the storage for iron, signalling molecule, and modulator of the immune response. METHODS Different electronic databases were searched in a non-systematic way to find out the literature of interest. RESULTS The level of ferritin rises in many inflammatory conditions including autoimmune disorders. However, in four inflammatory diseases (i.e., adult-onset Still's diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and sepsis), high levels of ferritin are observed suggesting it as a remarkable biomarker and pathological involvement in these diseases. Acting as an acute phase reactant, ferritin is also involved in the cytokine-associated modulator of the immune response as well as a regulator of cytokine synthesis and release which are responsible for the inflammatory storm. CONCLUSION This review article presents updated information on the role of ferritin in inflammatory and autoimmune diseases with an emphasis on hyperferritinaemic syndrome.
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Iron Deficiency in Heart Failure: An Overview.
von Haehling, S, Ebner, N, Evertz, R, Ponikowski, P, Anker, SD
JACC. Heart failure. 2019;(1):36-46
Abstract
Iron deficiency is an extremely common comorbidity in patients with heart failure, affecting up to 50% of all ambulatory patients. It is associated with reduced exercise capacity and physical well-being and reduced quality of life. Cutoff values have been identified for diagnosing iron deficiency in heart failure with reduced ejection fraction as serum ferritin, <100 μg/l, or ferritin, 100 to 300 μg/l, with transferrin saturation of <20%. Oral iron products have been shown to have little efficacy in heart failure, where the preference is intravenous iron products. Most clinical studies have been performed using ferric carboxymaltose with good efficacy in terms of improvements in 6-min walk test distance, peak oxygen consumption, quality of life, and improvements in New York Heart Association functional class. Data from meta-analyses also suggest beneficial effects for hospitalization rates for heart failure and reduction in cardiovascular mortality rates. A prospective trial to investigate effects on morbidity and mortality is currently ongoing. This paper highlights current knowledge of the pathophysiology of iron deficiency in heart failure, its prevalence and clinical impact, and its possible treatment options.
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Investigation and management of a raised serum ferritin.
Cullis, JO, Fitzsimons, EJ, Griffiths, WJ, Tsochatzis, E, Thomas, DW, ,
British journal of haematology. 2018;(3):331-340
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Abstract
Serum ferritin level is one of the most commonly requested investigations in both primary and secondary care. Whilst low serum ferritin levels invariably indicate reduced iron stores, raised serum ferritin levels can be due to multiple different aetiologies, including iron overload, inflammation, liver or renal disease, malignancy, and the recently described metabolic syndrome. A key test in the further investigation of an unexpected raised serum ferritin is the serum transferrin saturation. This guideline reviews the investigation and management of a raised serum ferritin level. The investigation and management of genetic haemochromatosis is not dealt with however and is the subject of a separate guideline.
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The effect of vegetarian diets on iron status in adults: A systematic review and meta-analysis.
Haider, LM, Schwingshackl, L, Hoffmann, G, Ekmekcioglu, C
Critical reviews in food science and nutrition. 2018;(8):1359-1374
Abstract
BACKGROUND Vegetarian diets exclude meat, seafood, and products containing these foods. Although the vegetarian lifestyle could lead to a better health status in adults, it may also bear risks for certain nutritional deficiencies. Cross-sectional studies and narrative reviews have shown that the iron status of vegetarians is compromised by the absence of highly bioavailable haem-iron in meatless diets and the inhibiting effect of certain components present in plant foods on non-haem iron bioavailability. METHODS The databases Pubmed, Scopus, Embase, and Cochrane CentralRegister of Controlled Trials were searched for studies comparing serum ferritin, as the major laboratory parameter for iron status of adult vegetarians with non-vegetarian control groups. A qualitative review was conducted as well as an inverse-variance random-effects meta-analysis to pool available data. In addition the effect of vegetarian diets according to gender was investigated with a subgroup analysis. The results were validated using a sensitivity analysis. RESULTS A total of 27 cross-sectional studies and three interventional studies were selected for the systematic review. The meta-analysis which combined data of 24 cross-sectional studies showed that adult vegetarians have significantly lower serum ferritin levels than their non-vegetarian controls (-29.71 µg/L, 95% CI [-39.69, -19.73], p < 0.01). Inclusion of semi-vegetarian diets did not change the results considerably (-23.27 µg/L, 95% CI [-29.77, -16.76], p < 0.01). The effects were more pronounced in men (-61.88 µg/L, 95% CI [-85.59, -38.17], p < 0.01) than in both premenopausal women (-17.70 μg/L, 95% CI [-29.80, -5.60], p < 0.01) and all women (-13.50 μg/L, 95% CI [-22.96, -4.04], p < 0.01), respectively. CONCLUSIONS In conclusion our results showed that vegetarians are more likely to have lower iron stores compared with non-vegetarians. However, since high iron stores are also a risk factor for certain non-communicable diseases, such as type 2 diabetes, it is recommended that not only vegetarians but also non-vegetarians should regularly control their iron status and improve their diet regarding the content and bioavailability of iron by consuming more plants and less meat.
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Adjusting ferritin concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project.
Namaste, SM, Rohner, F, Huang, J, Bhushan, NL, Flores-Ayala, R, Kupka, R, Mei, Z, Rawat, R, Williams, AM, Raiten, DJ, et al
The American journal of clinical nutrition. 2017;(Suppl 1):359S-371S
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Abstract
Background: The accurate estimation of iron deficiency is important in planning and implementing interventions. Ferritin is recommended as the primary measure of iron status, but interpretability is challenging in settings with infection and inflammation.Objective: We assessed the relation between ferritin concentrations and inflammation and malaria in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y) and investigated adjustment algorithms to account for these effects.Design: Cross-sectional data from 15 surveys for PSC (n = 27,865) and 8 surveys for WRA (24,844), from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and combined with the use of a meta-analysis. Several approaches were explored to estimate depleted iron stores (ferritin concentration <12 μg/L in PSC and <15 μg/L in WRA) in inflammation and malaria settings as follows: 1) increase ferritin-concentration cutoff to <30 μg/L; 2) exclude individuals with C-reactive protein (CRP) concentrations >5 mg/L or α-1-acid glycoprotein (AGP) concentrations >1 g/L; 3) apply arithmetic correction factors; and 4) use a regression correction approach.Results: Depleted iron-store estimates incrementally increased as CRP and AGP deciles decreased (4% compared with 30%, and 6% compared with 29% from highest compared with lowest CRP deciles for pooled PSC and WRA, respectively, with similar results for AGP). Depending on the approach used to adjust for inflammation (CRP plus AGP), the estimated prevalence of depleted iron stores increased by 7-25 and 2-8 absolute median percentage points for PSC and WRA, respectively, compared with unadjusted values. Adjustment for malaria in addition to CRP and AGP did not substantially change the estimated prevalence of depleted iron stores.Conclusions: Our results lend support for the use of internal regression correction to estimate the prevalence of depleted iron stores in regions with inflammation. This approach appears to mathematically reflect the linear relation of ferritin concentrations with acute-phase proteins. More research is warranted to validate the proposed approaches, but this study contributes to the evidence base to guide decisions about how and when to adjust ferritin for inflammation.