Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory ...hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.
The discovery of the iron-regulatory hormone hepcidin in 2001 has revolutionized our understanding of iron disorders, and its measurement should advance diagnosis/treatment of these conditions. ...Although several assays have been developed, a gold standard is still lacking, and efforts toward harmonization are ongoing. Nevertheless, promising applications can already be glimpsed, ranging from the use of hepcidin levels for diagnosing iron-refractory iron deficiency anemia to global health applications such as guiding safe iron supplementation in developing countries with high infection burden.
Iron deficiency Pasricha, Sant-Rayn; Tye-Din, Jason; Muckenthaler, Martina U ...
The Lancet (British edition),
01/2021, Letnik:
397, Številka:
10270
Journal Article
Recenzirano
Iron deficiency is one of the leading contributors to the global burden of disease, and particularly affects children, premenopausal women, and people in low-income and middle-income countries. ...Anaemia is one of many consequences of iron deficiency, and clinical and functional impairments can occur in the absence of anaemia. Iron deprivation from erythroblasts and other tissues occurs when total body stores of iron are low or when inflammation causes withholding of iron from the plasma, particularly through the action of hepcidin, the main regulator of systemic iron homoeostasis. Oral iron therapy is the first line of treatment in most cases. Hepcidin upregulation by oral iron supplementation limits the absorption efficiency of high-dose oral iron supplementation, and of oral iron during inflammation. Modern parenteral iron formulations have substantially altered iron treatment and enable rapid, safe total-dose iron replacement. An underlying cause should be sought in all patients presenting with iron deficiency: screening for coeliac disease should be considered routinely, and endoscopic investigation to exclude bleeding gastrointestinal lesions is warranted in men and postmenopausal women presenting with iron deficiency anaemia. Iron supplementation programmes in low-income countries comprise part of the solution to meeting WHO Global Nutrition Targets.
This study explored the relationship between serum ferritin and hepcidin in athletes. Baseline serum ferritin levels of 54 athletes from the control trial of five investigations conducted in our ...laboratory were considered; athletes were grouped according to values <30 μg/L (SF<30), 30-50 μg/L (SF30-50), 50-100 μg/L (SF50-100), or >100 μg/L (SF>100). Data pooling resulted in each athlete completing one of five running sessions: (1) 8 × 3 min at 85% vVO2peak; (2) 5 × 4 min at 90% vVO2peak; (3) 90 min continuous at 75% vVO2peak; (4) 40 min continuous at 75% vVO2peak; (5) 40 min continuous at 65% vVO2peak. Athletes from each running session were represented amongst all four groups; hence, the mean exercise duration and intensity were not different (p>0.05). Venous blood samples were collected pre-, post- and 3 h post-exercise, and were analysed for serum ferritin, iron, interleukin-6 (IL-6) and hepcidin-25. Baseline and post-exercise serum ferritin levels were different between groups (p<0.05). There were no group differences for pre- or post-exercise serum iron or IL-6 (p>0.05). Post-exercise IL-6 was significantly elevated compared to baseline within each group (p<0.05). Pre- and 3 h post-exercise hepcidin-25 was sequentially greater as the groups baseline serum ferritin levels increased (p<0.05). However, post-exercise hepcidin levels were only significantly elevated in three groups (SF30-50, SF50-100, and SF>100; p<0.05). An athlete's iron stores may dictate the baseline hepcidin levels and the magnitude of post-exercise hepcidin response. Low iron stores suppressed post-exercise hepcidin, seemingly overriding any inflammatory-driven increases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Iron supplements acutely increase hepcidin, but the duration and magnitude of the increase, its dose dependence, and its effects on subsequent iron absorption have not been characterized in humans. ...Better understanding of these phenomena might improve oral iron dosing schedules. We investigated whether the acute iron-induced increase in hepcidin influences iron absorption of successive daily iron doses and twice-daily iron doses. We recruited 54 nonanemic young women with plasma ferritin ≤20 µg/L and conducted: (1) a dose-finding investigation with 40-, 60-, 80-, 160-, and 240-mg labeled Fe as 57Fe-, 58Fe-, or 54Fe-FeSO4 given at 8:00 am fasting on 1 or on 2 consecutive days (study 1, n = 25; study 2, n = 16); and (2) a study giving three 60-mg Fe doses (twice-daily dosing) within 24 hours (study 3, n = 13). In studies 1 and 2, 24 hours after doses ≥60 mg, serum hepcidin was increased (P < .01) and fractional iron absorption was decreased by 35% to 45% (P < .01). With increasing dose, fractional absorption decreased (P < .001), whereas absolute absorption increased (P < .001). A sixfold increase in iron dose (40-240 mg) resulted in only a threefold increase in iron absorbed (6.7-18.1 mg). In study 3, total iron absorbed from 3 doses (2 mornings and an afternoon) was not significantly greater than that from 2 morning doses. Providing lower dosages (40-80 mg Fe) and avoiding twice-daily dosing maximize fractional absorption. The duration of the hepcidin response supports alternate day supplementation, but longer-term effects of these schedules require further investigation. These clinical trials were registered at www.ClinicalTrials.gov as #NCT01785407 and #NCT02050932.
•Iron supplements at doses of 60 mg Fe as FeSO4 or higher increase hepcidin for up to 24 hours and are associated with lower iron absorption on the following day.•The soluble transferrin receptor/ferritin ratio and hepcidin are equivalent predictors of iron absorption from supplements.
Recent trials have questioned the safety of untargeted oral iron supplementation in developing regions. Excess of luminal iron could select for enteric pathogens at the expense of beneficial ...commensals in the human gut microflora, thereby increasing the incidence of infectious diseases. The objective of the current study was to determine the effect of high iron availability on virulence traits of prevalent enteric pathogens at the host-microbe interface. A panel of enteric bacteria was cultured under iron-limiting conditions and in the presence of increasing concentrations of ferric citrate to assess the effect on bacterial growth, epithelial adhesion, invasion, translocation and epithelial damage in vitro. Translocation and epithelial integrity experiments were performed using a transwell system in which Caco-2 cells were allowed to differentiate to a tight epithelial monolayer mimicking the intestinal epithelial barrier. Growth of Salmonella typhimurium and other enteric pathogens was increased in response to iron. Adhesion of S. typhimurium to epithelial cells markedly increased when these bacteria were pre-incubated with increasing iron concentration (P = 0.0001), whereas this was not the case for the non-pathogenic Lactobacillus plantarum (P = 0.42). Cellular invasion and epithelial translocation of S. typhimurium followed the trend of increased adhesion. Epithelial damage was increased upon incubation with S. typhimurium or Citrobacter freundii that were pre-incubated under iron-rich conditions. In conclusion, our data fit with the consensus that oral iron supplementation is not without risk as iron could, in addition to inducing pathogenic overgrowth, also increase the virulence of prevalent enteric pathogens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
Iron deficiency is common in patients with heart failure and associated with a poor cardiac function and higher mortality. How iron deficiency impairs cardiac function on a cellular level in the ...human setting is unknown. This study aims to determine the direct effects of iron deficiency and iron repletion on human cardiomyocytes.
Methods and results
Human embryonic stem cell‐derived cardiomyocytes were depleted of iron by incubation with the iron chelator deferoxamine (DFO). Mitochondrial respiration was determined by Seahorse Mito Stress test, and contractility was directly quantified using video analyses according to the BASiC method. The activity of the mitochondrial respiratory chain complexes was examined using spectrophotometric enzyme assays. Four days of iron depletion resulted in an 84% decrease in ferritin (P < 0.0001) and significantly increased gene expression of transferrin receptor 1 and divalent metal transporter 1 (both P < 0.001). Mitochondrial function was reduced in iron‐deficient cardiomyocytes, in particular ATP‐linked respiration and respiratory reserve were impaired (both P < 0.0001). Iron depletion affected mitochondrial function through reduced activity of the iron–sulfur cluster containing complexes I, II and III, but not complexes IV and V. Iron deficiency reduced cellular ATP levels by 74% (P < 0.0001) and reduced contractile force by 43% (P < 0.05). The maximum velocities during both systole and diastole were reduced by 64% and 85%, respectively (both P < 0.001). Supplementation of transferrin‐bound iron recovered functional and morphological abnormalities within 3 days.
Conclusion
Iron deficiency directly affects human cardiomyocyte function, impairing mitochondrial respiration, and reducing contractility and relaxation. Restoration of intracellular iron levels can reverse these effects.
In-home iron fortification for infants in developing countries is recommended for control of anaemia, but low absorption typically results in >80% of the iron passing into the colon. Iron is ...essential for growth and virulence of many pathogenic enterobacteria. We determined the effect of high and low dose in-home iron fortification on the infant gut microbiome and intestinal inflammation.
We performed two double-blind randomised controlled trials in 6-month-old Kenyan infants (n=115) consuming home-fortified maize porridge daily for 4 months. In the first, infants received a micronutrient powder (MNP) containing 2.5 mg iron as NaFeEDTA or the MNP without iron. In the second, they received a different MNP containing 12.5 mg iron as ferrous fumarate or the MNP without the iron. The primary outcome was gut microbiome composition analysed by 16S pyrosequencing and targeted real-time PCR (qPCR). Secondary outcomes included faecal calprotectin (marker of intestinal inflammation) and incidence of diarrhoea. We analysed the trials separately and combined.
At baseline, 63% of the total microbial 16S rRNA could be assigned to Bifidobacteriaceae but there were high prevalences of pathogens, including Salmonella Clostridium difficile, Clostridium perfringens, and pathogenic Escherichia coli. Using pyrosequencing, +FeMNPs increased enterobacteria, particularly Escherichia/Shigella (p=0.048), the enterobacteria/bifidobacteria ratio (p=0.020), and Clostridium (p=0.030). Most of these effects were confirmed using qPCR; for example, +FeMNPs increased pathogenic E. coli strains (p=0.029). +FeMNPs also increased faecal calprotectin (p=0.002). During the trial, 27.3% of infants in +12.5 mgFeMNP required treatment for diarrhoea versus 8.3% in -12.5 mgFeMNP (p=0.092). There were no study-related serious adverse events in either group.
In this setting, provision of iron-containing MNPs to weaning infants adversely affects the gut microbiome, increasing pathogen abundance and causing intestinal inflammation.
NCT01111864.
Mass spectrometry (MS)-based assays for the quantification of the iron regulatory hormone hepcidin are pivotal to discriminate between the bioactive 25-amino acid form that can effectively block the ...sole iron transporter ferroportin and other naturally occurring smaller isoforms without a known role in iron metabolism. Here we describe the design, validation and use of a novel stable hepcidin-25(+40) isotope as internal standard for quantification. Importantly, the relative large mass shift of 40 Da makes this isotope also suitable for easy-to-use medium resolution linear time-of-flight (TOF) platforms. As expected, implementation of hepcidin-25(+40) as internal standard in our weak cation exchange (WCX) TOF MS method yielded very low inter/intra run coefficients of variation. Surprisingly, however, in samples from kidney disease patients, we detected a novel peak (m/z 2673.9) with low intensity that could be identified as hepcidin-24 and had previously remained unnoticed due to peak interference with the formerly used internal standard. Using a cell-based bioassay it was shown that synthetic hepcidin-24 was, like the -22 and -20 isoforms, a significantly less potent inducer of ferroportin degradation than hepcidin-25. During prolonged storage of plasma at room temperature, we observed that a decrease in plasma hepcidin-25 was paralleled by an increase in the levels of the hepcidin-24, -22 and -20 isoforms. This provides first evidence that all determinants for the conversion of hepcidin-25 to smaller inactive isoforms are present in the circulation, which may contribute to the functional suppression of hepcidin-25, that is significantly elevated in patients with renal impairment. The present update of our hepcidin TOF MS assay together with improved insights in the source and preparation of the internal standard, and sample stability will further improve our understanding of circulating hepcidin and pave the way towards further optimization and standardization of plasma hepcidin assays.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Anemia is highly prevalent, especially in older individuals. In selected populations, anemia has been reported to be associated with impaired survival and health-related quality of life. However, ...data on this impact in the general population are rare. Furthermore, discussions on the optimal definition of anemia have not been conclusive. We investigated these issues using survival data, scores from a health-related quality of life questionnaire (RAND-36), and hemoglobin concentration from 138670 subjects, aged 18-93 years, participating in the Lifelines cohort. Anemia was defined according to World Health Organization criteria and was further subclassified in participants over 60 years old. Anemia was present in 5510 (4.0%) of all 138670 subjects and 516 (2.8%) in the 18667 individuals older than 60 years. Anemia had no impact on overall survival and limited impact on health-related quality of life in individuals less than 60 years old. In contrast, in individuals over 60 years old anemia significantly impaired overall survival and health-related quality of life. The lower health-related quality of life was mainly observed in subscales representing physical functioning. Although consensus on the subclassification of anemia is lacking, our data suggest that particularly anemia of chronic inflammation was associated with worse overall survival and decreased health-related quality of life. Multivariate models confirmed that anemia was an independent risk factor for decreased health-related quality of life in older individuals. Finally, women with a hemoglobin concentration between 12.0-13.0 g/dL (considered anemia in men, but not in women) experienced a significantly lower health-related quality of life. This large, prospective, population-based study indicates that anemia is associated with worse overall survival and health-related quality of life in older individuals, but not in younger individuals. The findings of this study challenge the definition of anemia in women over 60 years old, and suggest that the optimal definition of anemia, in the perspective of health-related quality of life, in women over 60 years old should be altered to a hemoglobin concentration below 13.0 g/dL (8.0 mmol/L), which is comparable to that in men.
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