Iron incorporation in red blood cells of pediatric sickle cell anemia: a stable isotope pilot investigation.

BACKGROUND/OBJECTIVES: Sickle cell anemia (SCA) is marked by hypoxia, inflammation, and secondary iron overload (IO), which potentially modulate hepcidin, the pivotal hormone governing iron homeostasis. The aim was to evaluate the iron incorporation in red blood cells (RBC) in SCA pediatric patients, considering the presence or absence of IO. SUBJECTS/METHODS: SCA children (n = 12; SCAtotal) ingested an oral stable iron isotope (57Fe) and iron incorporation in RBC was measured after 14 days. Patients with ≥1000 ng/mL serum ferritin were considered to present IO (SCAio+; n = 4) while the others were classified as being without IO (SCAio-; n = 8). Liver iron concentration (LIC) was determined by Magnetic Resonance Imaging (MRI) T2* method. RESULTS: The SCAio+ group had lower iron incorporation (mean ± SD: 0.166 ± 0.04 mg; 3.33 ± 0.757%) than SCAio- patients (0.746 ± 0.303 mg; 14.9 ± 6.05%) (p = 0.024). Hepcidin was not different between groups. Iron incorporation was inversely associated with serum ferritin level (SCAtotal group: r = -0.775, p = 0.041; SCAio- group: r = -0.982; p = 0.018) and sickle hemoglobin (HbS) presented positive correlation with iron incorporation (r = 0.991; p = 0.009) in SCAio- group. LIC was positively associated with ferritin (SCAtotal: r = 0.921; p = 0.026) and C reactive protein (SCAio+: r = 0.999; p = 0.020). CONCLUSION: SCAio+ group had lower iron incorporation in RBC than SCAio- group, suggesting that they may not need to reduce their intake of iron-rich food, as usually recommended. Conversely, a high percentage of HbS may indirectly exacerbate hypoxia and seems to increase iron incorporation in RBC. TRIAL REGISTRATION: This trial was registered at www.ensaiosclinicos.gov.br . Identifier RBR-4b7v8pt.

Iron absorption in adults with sickle cell anemia: a stable-isotope approach.

PURPOSE: Iron absorption in sickle cell anemia (SCA) remains unclear and studies in adults with SCA are scarce. The aim of this study was to evaluate the iron absorption SCA adults and its association with iron status and hepcidin concentration. METHODS: SCA patients (n = 13; SCAtotal) and control participants (n = 10) ingested an oral stable iron isotope (57Fe). Iron absorption was measured by inductively coupled plasma mass spectrometry (ICP-MS) 14 days after isotope administration. Patients with ≥ 1000 ng/mL serum ferritin were considered to present iron overload (IO) (SCAio+; n = 3) and others classified without IO (SCAio-; n = 10). RESULTS: Iron absorption in the control group ranged from 0.3 to 26.5% (median = 0.9%), while it varied from 0.3 to 5.4% in SCAio+ (median = 0.5%) and from 0.3 to 64.2% in the SCAio- (median = 6.9%). Hepcidin median values were 14.1 ng/mL (3.0-31.9 ng/mL) in SCAio-, 6.2 ng/mL (3.3-7.8 ng/mL) in SCAio + and 6.2 ng/mL (0.6-9.3 ng/mL) in control. Iron absorption was associated with ferritin level (r = - 0.641; p = 0.018) and liver iron concentration (LIC; r = - 0.786; p = 0.036) in the SCAtotal group. CONCLUSION: Our data suggest that SCAio- individuals may be at risk of developing primary IO. Simultaneously, secondary IO may induce physiological adaptation, resulting in reduced iron absorption. Further studies evaluating intestinal iron absorption using larger sample sizes should be conducted to help establish a safe nutrition approach to be adopted and to ensure the security of food-fortifying public policies for these patients. TRIAL REGISTRATION: This trial was registered at www.ensaiosclinicos.gov.br (Identifier RBR-4b7v8pt).

Novel bioanalytical strategy using isotope pattern deconvolution and ICP-QMS for the study of iron incorporation in erythrocytes: An insight to better assessment.

Iron is an essential element for human life and its nutritional status in the human body is directly linked to human health. More than 1015 atoms of iron per second are necessary for the maintenance of haemoglobin formation. To predict iron bioavailability three approaches are normally employed: (a) faecal recovery; (b) plasma appearance; and (c) erythrocyte incorporation (the most used). Isotope Pattern Deconvolution (IPD) is a mathematical tool that allows the isolation of distinct isotope signatures from mixtures of natural abundance and enriched tracers. In this work we propose a novel strategy to assess erythrocyte iron incorporation, based on the use of an iron stable isotope (57Fe) and the IPD concept. This strategy allows direct calculation of the exogenous concentration of 57Fe incorporated into RBCs after supplementation. In this way, to determine the mass of iron incorporated into erythrocytes, the unique prediction that must be made is the blood volume, estimate to reproduce the natural dilution of the tracer (57Fe) in the blood. This novel bioanalytical approach was applied for the measurements of iron incorporation and further iron absorption studies in humans, using a group of twelve healthy participants, that should be further evaluated for the assessment of other chemical elements that could be of health concerns and directly impact society.

Association of vitamin A with anemia and serum hepcidin levels in children aged 6 to 59 mo.

OBJECTIVE: This study evaluates the association of serum retinol, hepcidin levels, and anemia in children. METHODS: This cross-sectional study included 312 children, ages 6 to 59 mo, from Rio de Janeiro, Brazil. The association between hepcidin and retinol levels, hematologic parameters, and body mass index (BMI) was analyzed using a generalized linear model with and without adjustment for C-reactive protein (CRP) level. Logistic regression analysis was used to test anemia as an outcome and serum retinol level as a predictive variable using the odds ratio (OR) function. RESULTS: Anemia was present in 14.6% of the children, 5.8% presented iron deficiency anemia, and 9.6% had vitamin A deficiency. The increase in serum retinol levels reduced the chances of anemia (OR = 0.13; confidence interval = 0.29-0.59). When CRP level was not adjusted for in the multiple regression analyses, retinol, ferritin levels, and BMI/age were predictors of serum hepcidin levels (ß = -3.36, 0.14, 1.02, respectively; P = 0.032). Accordingly, serum retinol levels were inversely associated with CRP levels (ß = -0.025 and P < 0.001). CONCLUSIONS: The association between serum retinol and hepcidin levels in children ages 6 to 59 mo seems to be dependent on inflammation. Taken together, the results reinforce the need for the development of further studies to better understand the relationship between vitamin A and anemia of inflammation.

The effect of food and nutrients on iron overload: what do we know so far?

There has been no established food and nutrition guidance for diseases characterized by the presence of iron overload (IOL) yet. Hepcidin is a hormone that diminishes iron bioavailability. Its levels increase in response to increased iron stores. Hence, IOL conditions could hypothetically trigger a self-regulatory mechanism for the reduction of the intestinal absorption of iron. In addition, some food substances may modulate intestinal iron absorption and may be useful in the dietary management of patients with IOL. This scoping review aimed to systematize studies that support dietary prescriptions for IOL patients. It was carried out according to the method proposed by the Joanna Briggs Institute and the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Although the need to restrict iron in the diet of individuals with hemochromatosis is quite clear, there is a consensus that IOL diminishes the rate of iron absorption. Reduced iron absorption is also present and has been reported in some diseases with transfusion IOL, in which serum hepcidin is usually high. The consumption of polyphenols and 6-shogaol seems to reduce iron absorption or serum ferritin concentration, while procyanidins do not cause any changes. Vitamin C deficiency is often found in IOL patients. However, vitamin C supplementation and alcohol consumption should be avoided not only because they increase iron absorption, but also because they provoke toxic oxidative reactions when the iron is excessive. Dietary approaches must consider the differences in the pathophysiology and treatment of IOL diseases.

Antioxidant nutrients and hemolysis in sickle cell disease.

Hemolysis is one of the main pathophysiological characteristics of sickle cell disease (SCD) and might cause or could be the result of oxidative stress. Antioxidants are studied in SCD due to their potential to ensure redox balance and minimize deleterious effects on erythrocyte membranes. The objective of this systematic review was to evaluate the efficacy of antioxidant nutrient supplementation on reducing hemolysis in SCD patients through randomized clinical trials. We conducted our study according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses and the Cochrane Handbook for Systematic Reviews of Interventions investigating whether antioxidants could improve the hemolytic status of SCD patients. This study included 587 articles published until April 2020. We reduced this pool to 12 articles by excluding duplicates, reviews, comments, and studies with non-human subjects. Omega-3 fatty acids, vitamin A, and zinc were the antioxidants that reportedly improved the indirect hemolysis parameters such as hemoglobin, hematocrit, mean corpuscular volume, or red blood cells. High-dose vitamin C and E supplementation worsened hemolysis, causing increased reticulocytes, lactate dehydrogenase, indirect bilirubin, and haptoglobin. More intervention studies especially high-quality controlled randomized clinical trials are needed to investigate the effects of antioxidant nutrients in reducing hemolysis in SCD.

Selenium Status and Hemolysis in Sickle Cell Disease Patients.

Sickle cell disease (SCD) is a genetic hemoglobinopathy characterized by chronic hemolysis. Chronic hemolysis is promoted by increased oxidative stress. Our hypothesis was that some antioxidant micronutrients (retinol, tocopherol, selenium, and zinc) would be determinant factors of the degree of hemolysis in SCD patients. We aimed to investigate the nutritional adequacy of these antioxidants and their relationships to hemolysis. The study included 51 adult SCD patients regularly assisted in two reference centers for hematology in the State of Rio de Janeiro, Brazil. Serum concentrations of retinol, alpha-tocopherol, selenium, and zinc were determined by high-performance liquid chromatography or atomic absorption spectrometry. Hematological parameters (complete blood count, reticulocyte count, hemoglobin, direct and indirect bilirubin, total bilirubin, lactate dehydrogenase) and inflammation markers (leukocytes and ultra-sensitive C-reactive protein) were analyzed. A linear regression model was used to test the associations between the variables. Most patients presented selenium deficiency and low selenium consumption. Linear regression analysis showed that selenium is the main determinant of hemolysis among the antioxidant nutrients analyzed. Thus, data from this study suggest that the nutritional care protocols for patients with SCD should include dietary sources of selenium in order to reduce the risk of hemolysis.

Serum Hepcidin Concentration in Individuals with Sickle Cell Anemia: Basis for the Dietary Recommendation of Iron.

Dietary iron requirements in patients with sickle cell disease (SCD) remain unclear. SCD is a neglected hemoglobinopathy characterized by intense erythropoietic activity and anemia. Hepcidin is the hormone mainly responsible for iron homeostasis and intestinal absorption. Intense erythropoietic activity and anemia may reduce hepcidin transcription. By contrast, iron overload and inflammation may induce it. Studies on SCD have not evaluated the role of hepcidin in the presence and absence of iron overload. We aimed to compare serum hepcidin concentrations among individuals with sickle cell anemia, with or without iron overload, and those without the disease. Markers of iron metabolism and erythropoietic activity such as hepcidin, ferritin, and growth differentiation factor 15 were evaluated. Three groups participated in the study: the control group, comprised of individuals without SCD (C); those with the disease but without iron overload (SCDw); and those with the disease and iron overload (SCDio). Results showed that hepcidin concentration was higher in the SCDio > C > SCDw group. These data suggest that the dietary iron intake of the SCDio group should not be reduced as higher hepcidin concentrations may reduce the intestinal absorption of iron.