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Ferritin - from iron, through inflammation and autoimmunity, to COVID-19.
Mahroum, N, Alghory, A, Kiyak, Z, Alwani, A, Seida, R, Alrais, M, Shoenfeld, Y
Journal of autoimmunity. 2022;:102778
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Abstract
While it took decades to arrive to a conclusion that ferritin is more than an indicator of iron storage level, it took a short period of time through the COVID-19 pandemic to wonder what the reason behind high levels of ferritin in patients with severe COVID-19 might be. Unsurprisingly, acute phase reactant was not a satisfactory explanation. Moreover, the behavior of ferritin in patients with severe COVID-19 and the subsequent high mortality rates in patients with high ferritin levels necessitated further investigations to understand the role of ferritin in the diseases. Ferritin was initially described to accompany various acute infections, both viral and bacterial, indicating an acute response to inflammation. However, with the introduction of the hyperferritinemic syndrome connecting four severe pathological conditions such as adult-onset Still's disease, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock added another aspect of ferritin where it could have a pathogenetic role rather than an extremely elevated protein only. In fact, suggesting that COVID-19 is a new member in the spectrum of hyperferritinemic syndrome besides the four mentioned conditions could hopefully direct further search on the pathogenetic role of ferritin. Doubtlessly, improving our understanding of those aspects of ferritin would enormously contribute to better coping with severe diseases in terms of treatment and prevention of complications. The origin, history, importance, and the advances of searching the role of ferritin in various pathological and clinical processes are presented hereby in our article. In addition, the implications of ferritin in COVID-19 are addressed.
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Higher CSF Ferritin Heavy-Chain (Fth1) and Transferrin Predict Better Neurocognitive Performance in People with HIV.
Kaur, H, Bush, WS, Letendre, SL, Ellis, RJ, Heaton, RK, Patton, SM, Connor, JR, Samuels, DC, Franklin, DR, Hulgan, T, et al
Molecular neurobiology. 2021;(10):4842-4855
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Abstract
HIV-associated neurocognitive disorder (HAND) remains prevalent despite antiretroviral therapy and involves white matter damage in the brain. Although iron is essential for myelination and myelin maintenance/repair, its role in HAND is largely unexplored. We tested the hypotheses that cerebrospinal fluid (CSF) heavy-chain ferritin (Fth1) and transferrin, proteins integral to iron delivery and myelination, are associated with neurocognitive performance in people with HIV (PWH). Fth1, transferrin, and the pro-inflammatory cytokines TNF-α and IL-6 were quantified in CSF at baseline (entry) in 403 PWH from a prospective observational study who underwent serial, comprehensive neurocognitive assessments. Associations of Fth1 and transferrin with Global Deficit Score (GDS)-defined neurocognitive performance at baseline and 30-42 months of follow-up were evaluated by multivariable regression. While not associated with neurocognitive performance at baseline, higher baseline CSF Fth1 predicted significantly better neurocognitive performance over 30 months in all PWH (p < 0.05), in PWH aged < 50 at 30, 36, and 42 months (all p < 0.05), and in virally suppressed PWH at all three visit time-points (all p < 0.01). Higher CSF transferrin was associated with superior neurocognitive performance at all visits, primarily in viremic individuals (all p < 0.05). All associations persisted after adjustment for neuro-inflammation. In summary, higher CSF Fth1 is neuroprotective over prolonged follow-up in all and virally suppressed PWH, while higher CSF transferrin may be most neuroprotective during viremia. We speculate that higher CSF levels of these critical iron-delivery proteins support improved myelination and consequently, neurocognitive performance in PWH, providing a rationale for investigating their role in interventions to prevent and/or treat HAND.
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A Review on Natural Sources Derived Protein Nanoparticles as Anticancer Agents.
Bhattacharya, T, Maishu, SP, Akter, R, Rahman, MH, Akhtar, MF, Saleem, A, Bin-Jumah, M, Kamel, M, Abdel-Latif, MA, Abdel-Daim, MM
Current topics in medicinal chemistry. 2021;(12):1014-1026
Abstract
Cancer notably carcinoma represents a prominent health challenge worldwide. A variety of chemotherapeutic agents are being used to deal with a variety of carcinomas. However, these delivering agents not only enter the targeted site but also affect normal tissues yielding poor therapeutic outcomes. Chemotherapeutic-associated problems are being attributed to drug non-specificity resulting from poor drug delivery systems. These problems are now being solved using nanomedicine, which entails using nanoparticles as drug delivery systems or nanocarriers. This nanoparticle-based drug delivery system enhances clinical outcomes by enabling targeted delivery, improving drug internalization, enhanced permeability, easy biodistribution, prolonged circulation and enhanced permeability rate, thereby improving the therapeutic effectiveness of several anticancer agents. Natural Protein-based Nanoparticles (PNPs) such as ferritin, lipoprotein, and lectins from natural sources have gained extensive importance at a scientific community level as nanovehicle for effective drug delivery and photo acoustic labeling replacing several synthetic nanocarriers that have shown limited therapeutic outcomes. The bioavailability of PNP, the chance of genetic engineering techniques to modify their biological properties made them one of the important raw material sources for drug delivery research. This current review highlighted different chemotherapeutic agents used in the treatment of some carcinomas. It also focused on the wide variety of natural protein sources derived nanoparticles (NPs) as anticancer delivery of agents for cancer therapy.
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Serum Ferritin and the Risk of Metabolic Syndrome: A Systematic Review and Dose-Response Meta-Analysis of Cross-sectional Studies.
Zhang, WCB, Xing, Y, Shao, B
Biomedical and environmental sciences : BES. 2021;(8):623-631
Abstract
OBJECTIVE This study aims to assess the dose-response relationship between serum ferritin (SF) and metabolic syndrome (MetS) in the two sexes. METHODS We searched for articles on PubMed, the Cochrane Library, EMBASE, and the Web of Science databases that were published from 1950 to 2020. The summary odds ratio ( OR) and 95% confidence interval ( CI) of the association between SF and MetS were estimated using a random-effects model through a meta-analysis. Based on the methods described by Greenland and Longnecker, we explored the dose-response relationship between the two sexes. RESULTS This study included 14 studies and 74,710 samples. The results of the classical meta-analysis showed that SF was positively associated with MetS ( OR = 1.77, 95% CI: 1.59-1.98). Regarding the components of MetS (8 studies included), the results showed that SF was positively associated with abdominal obesity ( OR = 1.42, 95% CI: 1.24-1.62), elevated fasting plasma glucose ( OR = 1.84, 95% CI: 1.50-2.25), elevated blood pressure ( OR = 1.17, 95% CI: 1.08-1.26), elevated triglycerides ( OR= 2.09, 95% CI: 1.72-2.54), and reduced high-density lipoprotein cholesterol ( OR = 1.33, 95% CI: 1.19-1.49). In the linear dose-response meta-analysis, the ORs of males, females, and postmenopausal females were 1.14 (95% CI: 1.13-1.16), 1.32 (95% CI: 1.26-1.39), and 1.34 (95% CI: 1.22-1.47), respectively. CONCLUSIONS Our study shows that SF is significantly and positively associated with MetS, and the risk in the male population is higher than that in the female population. This finding also supports the recommendation of using SF as an early warning marker of MetS.
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Brain iron concentrations in the pathophysiology of children with attention deficit/hyperactivity disorder: a systematic review.
Degremont, A, Jain, R, Philippou, E, Latunde-Dada, GO
Nutrition reviews. 2021;(5):615-626
Abstract
CONTEXT Attention deficit/hyperactivity disorder (ADHD) is a neurological disorder associated with iron dysregulation in children. Although previous focus was on examining systemic iron status, brain iron content may be a more reliable biomarker of the disorder. OBJECTIVE This systematic review examines whether children with ADHD have lower serum as well as brain iron concentrations, compared with healthy control subjects (HCS). DATA SOURCES A systematic literature search was conducted in Medline via PubMed, the Cochrane Library, Web of Science, Embase. and Ovid for papers published between 2000 and June 7, 2019. DATA EXTRACTION Studies were included if the mean difference of iron concentration, measured as serum iron, serum ferritin, or brain iron, between children with ADHD and HCS was an outcome measure. DATA ANALYSIS Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Risks of bias within and between studies were assessed using the quality assessment tools of the National Institutes of Health. Of 599 records screened, 20 case-control studies met the inclusion criteria. In 10 of 18 studies in which serum ferritin concentration was assessed, and 2 of 10 studies that assessed serum iron, a significant difference between children with ADHD and HCS was observed. Results of systemic iron levels were inconsistent. In 3 studies in which brain iron concentration was assessed, a statistically significant, lower thalamic iron concentration was found in children with ADHD than in HCS. CONCLUSION The evidence, though limited, reveals that brain iron rather than systemic iron levels may be more associated with the pathophysiology of ADHD in children. Larger, longitudinal, magnetic resonance imaging studies are needed to examine any correlations of iron deficiency in specific brain regions and symptoms of ADHD.
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Understanding increased ferritin levels in pediatric ECMO patients.
Weber, Z, Sam, A, Pena, A, Henderson, C, McCurnin, D, Bhalala, U, Garcia, R, King, J, Carr, N
Blood cells, molecules & diseases. 2021;:102617
Abstract
Abnormally high serum ferritin levels have been reported during pediatric ECMO, attributed to frequent red blood cell transfusion and suggestive of iron overload. However, the utility of ferritin for diagnosing iron overload is complicated by its response as an acute-phase reactant. In this study, we aimed to assess the utility of ferritin for diagnosing ECMO-related iron overload, with secondary aims of understanding its relationship with inflammation and erythropoiesis. Ferritin was elevated in all pediatric ECMO runs (median 459 ng/ml, IQR = 327.3-694.4). While intermittent elevations in serum iron were observed, all normalized prior to decannulation. Unreported previously, erythropoietin (EPO) remained well above normative values prior to and throughout ECMO runs, despite frequent transfusion and exposure to hyperoxia. Ferritin correlated poorly with serum iron [r(80) = 0.05, p = 0.65], but correlated well with IL-6 [r(76) = 0.48, p < 0.001] and EPO [r(81) = 0.55, p < 0.001]. We suggest that serum ferritin is a poor biomarker of iron overload in ECMO patients, and that future investigation into its relationship with EPO is warranted.
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Serum or plasma ferritin concentration as an index of iron deficiency and overload.
Garcia-Casal, MN, Pasricha, SR, Martinez, RX, Lopez-Perez, L, Peña-Rosas, JP
The Cochrane database of systematic reviews. 2021;(5):CD011817
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Abstract
BACKGROUND Reference standard indices of iron deficiency and iron overload are generally invasive, expensive, and can be unpleasant or occasionally risky. Ferritin is an iron storage protein and its concentration in the plasma or serum reflects iron stores; low ferritin indicates iron deficiency, while elevated ferritin reflects risk of iron overload. However, ferritin is also an acute-phase protein and its levels are elevated in inflammation and infection. The use of ferritin as a diagnostic test of iron deficiency and overload is a common clinical practice. OBJECTIVES To determine the diagnostic accuracy of ferritin concentrations (serum or plasma) for detecting iron deficiency and risk of iron overload in primary and secondary iron-loading syndromes. SEARCH METHODS We searched the following databases (10 June 2020): DARE (Cochrane Library) Issue 2 of 4 2015, HTA (Cochrane Library) Issue 4 of 4 2016, CENTRAL (Cochrane Library) Issue 6 of 12 2020, MEDLINE (OVID) 1946 to 9 June 2020, Embase (OVID) 1947 to week 23 2020, CINAHL (Ebsco) 1982 to June 2020, Web of Science (ISI) SCI, SSCI, CPCI-exp & CPCI-SSH to June 2020, POPLINE 16/8/18, Open Grey (10/6/20), TRoPHI (10/6/20), Bibliomap (10/6/20), IBECS (10/6/20), SCIELO (10/6/20), Global Index Medicus (10/6/20) AIM, IMSEAR, WPRIM, IMEMR, LILACS (10/6/20), PAHO (10/6/20), WHOLIS 10/6/20, IndMED (16/8/18) and Native Health Research Database (10/6/20). We also searched two trials registers and contacted relevant organisations for unpublished studies. SELECTION CRITERIA We included all study designs seeking to evaluate serum or plasma ferritin concentrations measured by any current or previously available quantitative assay as an index of iron status in individuals of any age, sex, clinical and physiological status from any country. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methods. We designed the data extraction form to record results for ferritin concentration as the index test, and bone marrow iron content for iron deficiency and liver iron content for iron overload as the reference standards. Two other authors further extracted and validated the number of true positive, true negative, false positive, false negative cases, and extracted or derived the sensitivity, specificity, positive and negative predictive values for each threshold presented for iron deficiency and iron overload in included studies. We assessed risk of bias and applicability using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. We used GRADE assessment to enable the quality of evidence and hence strength of evidence for our conclusions. MAIN RESULTS Our search was conducted initially in 2014 and updated in 2017, 2018 and 2020 (10 June). We identified 21,217 records and screened 14,244 records after duplicates were removed. We assessed 316 records in full text. We excluded 190 studies (193 records) with reasons and included 108 studies (111 records) in the qualitative and quantitative analysis. There were 11 studies (12 records) that we screened from the last search update and appeared eligible for a future analysis. We decided to enter these as awaiting classification. We stratified the analysis first by participant clinical status: apparently healthy and non-healthy populations. We then stratified by age and pregnancy status as: infants and children, adolescents, pregnant women, and adults. Iron deficiency We included 72 studies (75 records) involving 6059 participants. Apparently healthy populations Five studies screened for iron deficiency in people without apparent illness. In the general adult population, three studies reported sensitivities of 63% to 100% at the optimum cutoff for ferritin, with corresponding specificities of 92% to 98%, but the ferritin cutoffs varied between studies. One study in healthy children reported a sensitivity of 74% and a specificity of 77%. One study in pregnant women reported a sensitivity of 88% and a specificity of 100%. Overall confidence in these estimates was very low because of potential bias, indirectness, and sparse and heterogenous evidence. No studies screened for iron overload in apparently healthy people. People presenting for medical care There were 63 studies among adults presenting for medical care (5042 participants). For a sample of 1000 subjects with a 35% prevalence of iron deficiency (of the included studies in this category) and supposing a 85% specificity, there would be 315 iron-deficient subjects correctly classified as having iron deficiency and 35 iron-deficient subjects incorrectly classified as not having iron deficiency, leading to a 90% sensitivity. Thresholds proposed by the authors of the included studies ranged between 12 to 200 µg/L. The estimated diagnostic odds ratio was 50. Among non-healthy adults using a fixed threshold of 30 μg/L (nine studies, 512 participants, low-certainty evidence), the pooled estimate for sensitivity was 79% with a 95% confidence interval of (58%, 91%) and specificity of 98%, with a 95% confidence interval of (91%, 100%). The estimated diagnostic odds ratio was 140, a relatively highly informative test. Iron overload We included 36 studies (36 records) involving 1927 participants. All studies concerned non-healthy populations. There were no studies targeting either infants, children, or pregnant women. Among all populations (one threshold for males and females; 36 studies, 1927 participants, very low-certainty evidence): for a sample of 1000 subjects with a 42% prevalence of iron overload (of the included studies in this category) and supposing a 65% specificity, there would be 332 iron-overloaded subjects correctly classified as having iron overload and 85 iron-overloaded subjects incorrectly classified as not having iron overload, leading to a 80% sensitivity. The estimated diagnostic odds ratio was 8. AUTHORS' CONCLUSIONS At a threshold of 30 micrograms/L, there is low-certainty evidence that blood ferritin concentration is reasonably sensitive and a very specific test for iron deficiency in people presenting for medical care. There is very low certainty that high concentrations of ferritin provide a sensitive test for iron overload in people where this condition is suspected. There is insufficient evidence to know whether ferritin concentration performs similarly when screening asymptomatic people for iron deficiency or overload.
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Serum ferritin levels in inflammation: a retrospective comparative analysis between COVID-19 and emergency surgical non-COVID-19 patients.
Banchini, F, Cattaneo, GM, Capelli, P
World journal of emergency surgery : WJES. 2021;(1):9
Abstract
BACKGROUND SARS-CoV-2 infection has spread worldwide, and the pathogenic mechanism is still under investigation. The presence of a huge inflammatory response, defined as "cytokine storm," is being studied in order to understand what might be the prognostic factors implicated in the progression of the infection, with ferritin being one of such markers. The role of ferritin as a marker of inflammation is already known, and whether it changes differently between COVID and non-COVID patients still remains unclear. The aim of this retrospective analysis is to understand whether the inflammatory process in these two types is different. METHODS In this retrospective analysis, we compared 17 patients affected by SARS-CoV-2, who had been admitted between February and April 2020 (group A) along with 30 patients admitted for acute surgical disease with SARS-CoV-2 negative swab (group B). A further subgroup of Covid negative patients with leukocytosis was compared to group A. RESULTS In group A, the median (interquartile range) serum ferritin was 674 (1284) ng/mL, and it was double the cutoff (300 ng/mL) in 9 out of 17 (52%). The median (IQR) value of ferritin level in the total blood samples of group B was 231, and in the subgroup with leucocytosis, 149 (145). Group A showed a significantly higher ferritin median level compared to the entire group B (two-tailed Mann-Whitney test, p < 0.0001) as well as to the subgroup with leucocytosis (p < 0.0014). CONCLUSIONS The role of iron metabolism appears to be directly involved in COVID infection. On the other hand, in the acute inflammation of patients admitted for surgery, and probably in other common phlogistic processes, iron modifications appear to be self-limited. However, our finding suggests the use of ferritin as a marker for COVID infection.
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Randomized Trial of Oral Iron and Diet Advice versus Diet Advice Alone in Young Children with Nonanemic Iron Deficiency.
Parkin, PC, Borkhoff, CM, Macarthur, C, Abdullah, K, Birken, CS, Fehlings, D, Koroshegyi, C, Maguire, JL, Mamak, E, Mamdani, M, et al
The Journal of pediatrics. 2021;:233-240.e1
Abstract
OBJECTIVE To compare the effects of 2 treatment options on neurodevelopmental and laboratory outcomes in young children with nonanemic iron deficiency. STUDY DESIGN A blinded, placebo-controlled, randomized trial of children 1-3 years with nonanemic iron deficiency (hemoglobin ≥110 g/L, serum ferritin <14 μg/L) was conducted in 8 primary care practices in Toronto, Canada. Interventions included ferrous sulfate or placebo for 4 months; all parents received diet advice. The primary outcome was the Early Learning Composite (ELC) using the Mullen Scales of Early Learning (mean 100, SD 15). Secondary outcomes included serum ferritin. Measurements were obtained at baseline and 4 and 12 months. Sample size was calculated to detect a between-group difference of 6-7 points in ELC. RESULTS At enrollment (n = 60), mean age was 24.2 (SD 7.4) months and mean serum ferritin was 10.0 (SD 2.4) μg/L. For ELC, the mean between-group difference at 4 months was 1.1 (95% CI -4.2 to 6.5) and at 12 months was 4.1 (95% CI -1.9 to 10.1). For serum ferritin, at 4 months, the mean between-group difference was 16.9 μg/L (95% CI 6.5 to 27.2), and no child randomized to ferrous sulfate had a serum ferritin <14 μg/L (0% vs 31%, P = .003). CONCLUSIONS For young children with nonanemic iron deficiency, treatment options include oral iron and/or diet advice. We remain uncertain about which option is superior with respect to cognitive outcomes; however, adding ferrous sulfate to diet advice resulted in superior serum ferritin outcomes after 4 months. Shared decision-making between practitioners and parents may be considered when selecting either option. TRIAL REGISTRATION Clinicaltrials.gov: NCT01481766.
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Impact of baseline serum ferritin and supplemental iron on altitude-induced hemoglobin mass response in elite athletes.
Koivisto-Mørk, AE, Svendsen, IS, Skattebo, Ø, Hallén, J, Paulsen, G
Scandinavian journal of medicine & science in sports. 2021;(9):1764-1773
Abstract
The present study explored the impact of pre-altitude serum (s)-ferritin and iron supplementation on changes in hemoglobin mass (ΔHbmass) following altitude training. Measures of Hbmass and s-ferritin from 107 altitude sojourns (9-28 days at 1800-2500 m) with world-class endurance athletes (males n = 41, females n = 25) were analyzed together with iron supplementation and self-reported illness. Altitude sojourns with a hypoxic dose [median (range)] of 1169 (912) km·h increased Hbmass (mean ± SD) 36 ± 38 g (3.7 ± 3.7%, p < 0.001) and decreased s-ferritin -11 (190) µg·L-1 (p = 0.001). Iron supplements [27 (191) mg·day-1 ] were used at 45 sojourns (42%), while only 11 sojourns (10%) were commenced with s-ferritin <35 µg/L. Hbmass increased by 4.6 ± 3.7%, 3.4 ± 3.3%, 4.2 ± 4.3%, and 2.9 ± 3.4% with pre-altitude s-ferritin ≤35 µg·L-1 , 36-50 µg·L-1 , 51-100 µg·L-1 , and >100 µg·L-1 , respectively, with no group difference (p = 0.400). Hbmass increased by 4.1 ± 3.9%, 3.0 ± 3.0% and 3.7 ± 4.7% without, ≤50 mg·day-1 or >50 mg·day-1 supplemental iron, respectively (p = 0.399). Linear mixed model analysis revealed no interaction between pre-altitude s-ferritin and iron supplementation on ΔHbmass (p = 0.906). However, each 100 km·h increase in hypoxic dose augmented ΔHbmass by an additional 0.4% (95% CI: 0.1-0.7%; p = 0.012), while each 1 g·kg-1 higher pre-altitude Hbmass reduced ΔHbmass by -1% (-1.6 to -0.5; p < 0.001), and illness lowered ΔHbmass by -5.7% (-8.3 to -3.1%; p < 0.001). In conclusion, pre-altitude s-ferritin or iron supplementation were not related to the altitude-induced increase in Hbmass (3.7%) in world-class endurance athletes with clinically normal iron stores.