Dietary nonheme iron is equally bioavailable from ferritin or ferrous sulfate in thalassemia intermedia.

Transfusion-independent patients with thalassemia intermedia (TI) develop fatal iron overload from excessive iron absorption triggered by ineffective erythropoiesis. More information about iron pharmacokinetics and nonheme, dietary iron absorption in such patients is needed to optimize management. To obtain more information, different forms of supplemental nonheme iron sources (ferritin and ferrous sulfate) were compared in 4 TI (hemoglobin <9 g/dL) and 6 control (hemoglobin 12-16 g/dL) patients. Serial serum iron concentrations were measured during the 24 hours following consumption of 1 mg/kg of elemental iron as ferritin or ferrous sulfate. Serum iron concentrations were also measured for one TI patient and one control patient 2 hours after the ingestion of 2 mg/kg of dietary iron in ferritin or ferrous sulfate. Maximum serum iron concentrations were observed 4 hours after the consumption of either dietary iron source. However, the serum iron values were unchanged for either dietary iron source, even at the higher doses of consumed iron. Thus, the bioavailability of dietary iron, either as ferritin or ferrous sulfate, was equivalent in both groups of patients. The pilot data support ferritin as an alternative dietary iron supplement to ferrous sulfate. ABBREVIATIONS: CRP C-reactive protein; Hb hemoglobin; IDA iron-deficient anemia; ICP inductively coupled plasma; IE ineffective erythropoiesis; SCD sickle cell disease; sTf transferrin saturation; TI thalassemia intermedia; TIBC total iron binding capacity; TM thalassemia major; Tf transferrin.

A nanoparticulate ferritin-core mimetic is well taken up by HuTu 80 duodenal cells and its absorption in mice is regulated by body iron.

BACKGROUND: Iron (Fe) deficiency anemia remains the largest nutritional deficiency disorder worldwide. How the gut acquires iron from nano Fe(III), especially at the apical surface, is incompletely understood. OBJECTIVE: We developed a novel Fe supplement consisting of nanoparticulate tartrate-modified Fe(III) poly oxo-hydroxide [here termed nano Fe(III)], which mimics the Fe oxide core of ferritin and effectively treats iron deficiency anemia in rats. METHODS: We determined transfer to the systemic circulation of nano Fe(III) in iron-deficient and iron-sufficient outbread Swiss mouse strain (CD1) mice with use of (59)Fe-labeled material. Iron deficiency was induced before starting the Fe-supplementation period through reduction of Fe concentrations in the rodent diet. A control group of iron-sufficient mice were fed a diet with adequate Fe concentrations throughout the study. Furthermore, we conducted a hemoglobin repletion study in which iron-deficient CD1 mice were fed for 7 d a diet supplemented with ferrous sulfate (FeSO4) or nano Fe(III). Finally, we further probed the mechanism of cellular acquisition of nano Fe(III) by assessing ferritin formation, as a measure of Fe uptake and utilization, in HuTu 80 duodenal cancer cells with targeted inhibition of divalent metal transporter 1 (DMT1) and duodenal cytochrome b (DCYTB) before exposure to the supplemented iron sources. Differences in gene expression were assessed by quantitative polymerase chain reaction. RESULTS: Absorption (means ± SEMs) of nano Fe(III) was significantly increased in iron-deficient mice (58 ± 19%) compared to iron-sufficient mice (18 ± 17%) (P = 0.0001). Supplementation of the diet with nano Fe(III) or FeSO4 significantly increased hemoglobin concentrations in iron-deficient mice (170 ± 20 g/L, P = 0.01 and 180 ± 20 g/L, P = 0.002, respectively). Hepatic hepcidin mRNA expression reflected the nonheme-iron concentrations of the liver and was also comparable for both nano Fe(III)- and FeSO4-supplemented groups, as were iron concentrations in the spleen and duodenum. Silencing of the solute carrier family 11 (proton-coupled divalent metal ion transporter), member 2 (Slc11a2) gene (DMT1) significantly inhibited ferritin formation from FeSO4 (P = 0.005) but had no effect on uptake and utilization of nano Fe(III). Inhibiting DCYTB with an antibody also had no effect on uptake and utilization of nano Fe(III) but significantly inhibited ferritin formation from ferric nitrilotriacetate chelate (Fe-NTA) (P = 0.04). Similarly, cellular ferritin formation from nano Fe(III) was unaffected by the Fe(II) chelator ferrozine, which significantly inhibited uptake and utilization from FeSO4 (P = 0.009) and Fe-NTA (P = 0.005). CONCLUSIONS: Our data strongly support direct nano Fe(III) uptake by enterocytes as an efficient mechanism of dietary iron acquisition, which may complement the known Fe(II)/DMT1 uptake pathway.

A nano-disperse ferritin-core mimetic that efficiently corrects anemia without luminal iron redox activity.

The 2-5 nm Fe(III) oxo-hydroxide core of ferritin is less ordered and readily bioavailable compared to its pure synthetic analogue, ferrihydrite. We report the facile synthesis of tartrate-modified, nano-disperse ferrihydrite of small primary particle size, but with enlarged or strained lattice structure (~2.7Å for the main Bragg peak versus 2.6Å for synthetic ferrihydrite). Analysis indicated that co-precipitation conditions can be achieved for tartrate inclusion into the developing ferrihydrite particles, retarding both growth and crystallization and favoring stabilization of the cross-linked polymeric structure. In murine models, gastrointestinal uptake was independent of luminal Fe(III) reduction to Fe(II) and, yet, absorption was equivalent to that of ferrous sulphate, efficiently correcting the induced anemia. This process may model dietary Fe(III) absorption and potentially provide a side effect-free form of cheap supplemental iron. From the clinical editor: Small size tartrate-modified, nano-disperse ferrihydrite was used for efficient gastrointestinal delivery of soluble Fe(III) without the risk for free radical generation in murine models. This method may provide a potentially side effect-free form iron supplementation.

Anaemia management in non-dialysis chronic kidney disease (CKD) patients: a multicentre prospective study in renal clinics.

BACKGROUND: Knowledge on anaemia management in non-dialysis chronic kidney disease (ND-CKD) patients regularly followed in renal clinics is scarce although being essential to identifying areas of therapeutic improvement. METHODS: We prospectively evaluated anaemia management in two visits, performed 6 months apart, in 755 prevalent ND-CKD stage 3b-5 patients followed in 19 nephrology clinics from ≥6 months. Anaemia was defined as severe (Hb <11 g/dL) or mild (Hb: 11-13.5 in males and 11-12 g/dL in females); iron deficiency (ID) was defined as transferrin saturation (TSAT) <20% and/or ferritin <100 ng/mL. Primary endpoint was the change of anaemia and ID prevalence between baseline and 6-month visit. Secondary endpoint was the prevalence of clinical inertia to either ESA or iron supplementation, that is, the lack of ESA or iron prescription despite Hb <11 g/dL or ID. RESULTS: Age was 69 ± 13 years and GFR 27.5 ± 10.0 mL/min/1.73 m(2); male gender, diabetes and prior cardiovascular disease were 57.2, 30.1 and 30.1%, respectively. Prevalence of severe and mild anaemia was 18.0 and 44.0% at baseline and remained unchanged at Month 6 (19.3 and 43.2%). ID was prevalent at both visits (60.1 and 60.9%). Clinical inertia to ESA was similar at baseline and at Month 6 (39.6 and 34.2%, respectively, P = 0.487) and it was less frequent than clinical inertia to iron therapy (75.7 and 72.0%, respectively). CONCLUSIONS: This study shows that anaemia prevalence is unexpectedly high in the setting of tertiary nephrology care. This was due to a persistent clinical inertia in the anaemia management, remarkable for iron supplementation and less critical, but still significant, for ESA treatment.

Study on iron availability from prepared soybean sprouts using an iron-deficient rat model.

During soya seeds germination in FeSO(4) solutions their phytoferritin content is multiplied. Prepared soybean sprouts have been proposed as a safe and easily available source of iron supplementation. The preparation was compared with FeSO(4) and ferritin isolates, using rats with induced iron deficiency anaemia. After the end of the 2-week supplementation experiment, it was observed that no statistically significant differences in haemoglobin concentration, mean corpuscular volume, mean corpuscular haemoglobin, and mean corpuscular haemoglobin concentration existed between those animals supplemented with sprouts enriched in ferritin, ferritin isolate and FeSO(4) and healthy animals forming the control group. Moreover, the examined preparation had a beneficial influence on the recreation of ferritin reserves in both the liver and the blood serum, and also did not induce negative alterations in general growth parameters of animals. Use of an easily obtainable ferritin iron source may be a profitable alternative in supplementation due to its wide availability and food preservative properties.

Iron deficiency in women: assessment, causes and consequences.

PURPOSE OF REVIEW: Iron deficiency is the most common nutritional disorder affecting about 20-25% of the world's population, predominantly children and women. There is emerging evidence that depletion of iron stores may have adverse consequences for adults even in the absence of anaemia. This raises issues about the most appropriate method of assessing iron status. RECENT FINDINGS: Although the effects of iron-deficiency anaemia are well characterized, emerging evidence suggests that iron deficiency without anaemia can have negative consequences in adults, particularly for neurocognitive outcomes. Iron deficiency is more likely in women of reproductive age because of menstrual blood loss. However, extremes of blood loss such as regular blood donation, diets of low bioavailability and the challenges of pregnancy all markedly increase the risk of iron deficiency. In addition, the physiological changes in pregnancy affect the normal reference ranges used in laboratory assessment. The use of haemoglobin as a marker of iron deficiency is limited by its low specificity and sensitivity and although the use of alternative biomarkers is becoming more common, interpreting results in conditions of chronic inflammation, including that associated with increased adiposity, needs more investigation. SUMMARY: By understanding the physiology of iron metabolism alongside the limitations and interpretation of biomarkers of iron deficiency, clinicians and nutritionists are better equipped to identify changes in iron balance and to further investigate the functional outcomes of iron deficiency.

Rationale and design of the oral HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets trial for the correction of anaemia in peritoneal dialysis patients (HEMATOCRIT trial).

BACKGROUND: The main hypothesis of this study is that oral heme iron polypeptide (HIP; Proferrin ES) administration will more effectively augment iron stores in erythropoietic stimulatory agent (ESA)-treated peritoneal dialysis (PD) patients than conventional oral iron supplementation (Ferrogradumet). METHODS: Inclusion criteria are peritoneal dialysis patients treated with darbepoietin alpha (DPO; Aranesp(R), Amgen) for >or= 1 month. Patients will be randomized 1:1 to receive either slow-release ferrous sulphate (1 tablet twice daily; control) or HIP (1 tablet twice daily) for a period of 6 months. The study will follow an open-label design but outcome assessors will be blinded to study treatment. During the 6-month study period, haemoglobin levels will be measured monthly and iron studies (including transferring saturation [TSAT] measurements) will be performed bi-monthly. The primary outcome measure will be the difference in TSAT levels between the 2 groups at the end of the 6 month study period, adjusted for baseline values using analysis of covariance (ANCOVA). Secondary outcome measures will include serum ferritin concentration, haemoglobin level, DPO dosage, Key's index (DPO dosage divided by haemoglobin concentration), and occurrence of adverse events (especially gastrointestinal adverse events). DISCUSSION: This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their peritoneal dialysis patients determine whether HIP administration more effectively augments iron stores in ESP-treated PD patients than conventional oral iron supplementation. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry number ACTRN12609000432213.

Effects of dietary factors on iron uptake from ferritin by Caco-2 cells.

Biofortification of staple foods with iron (Fe) in the form of ferritin (Ft) is now possible, both by conventional plant breeding methods and transgenic approaches. Ft-Fe from plants and animals is absorbed well (25-30%) by human subjects, but little is known about dietary factors affecting its absorption. We used human intestinal Caco-2 cells and compared Fe absorption from animal Ft and FeSO4 to determine the effects of inhibitors and enhancers, such as phytic acid, ascorbic acid, tannic acid, calcium and heme. When postconfluent cells were coincubated with 59Fe-labeled (1 microM) FeSO4 and dietary factors, at different molar ratios of dietary factor to Fe (phytic acid:Fe, 10:1; ascorbic acid:Fe, 50:1; tannic acid:Fe, 50:1; calcium:Fe, 10:1 and hemin:Fe, 10:1), all inhibited uptake from FeSO4, except ascorbate, confirming earlier studies. In contrast, these dietary factors had little or no effect on Fe uptake from undigested Ft or Ft digested in vitro at pH 4, except tannins. However, results after in vitro digestion of Ft at pH 2 were similar to those obtained for FeSO4. These results suggest that Fe uptake occurs from both undigested as well as digested Ft but, possibly, via different mechanisms. The Fe-Ft stability shown here could minimize Fe-induced oxidation of Fe-supplemented food products.

Weekly administration of high-dose sodium ferric gluconate is safe and effective in peritoneal dialysis patients.

This report describes the safety and efficacy of high-dose sodium ferric gluconate in 18 peritoneal dialysis (PD) patients. Nine patients received low-dose (125 mg) and 9 patients received high-dose (250 mg) sodium ferric gluconate once per week for 8 or 4 weeks, respectively, followed by a maintenance dose once every 4 weeks. Patients in both groups had low iron saturation before treatment (hemoglobin [Hgb] < 11 g/dl, transferrin saturation [TSAT] approximately 20%, and serum ferritin < 250 ng/ml). After treatment, TSAT and ferritin significantly increased in both the low-dose (ferritin 465 +/- 292 ng/ml and TSAT 33.5 +/- 6.9%) and high-dose (ferritin 622 +/- 339 ng/ml and TSAT 35.0 +/- 25.7%) groups compared to baseline. Hemoglobin levels also increased in both groups, but this was not statistically significant. No adverse reactions or transferrin oversaturation with high-dose sodium ferric gluconate were observed. In conclusion, high-dose sodium ferric gluconate was safe, convenient, and effective in treating iron deficiency in PD patients.

Iron supplementation in pregnancy: is less enough? A randomized, placebo controlled trial of low dose iron supplementation with and without heme iron.

BACKGROUND: The purpose of the present study was to evaluate the efficacy of low dose iron supplementation with and without a heme component, prescribed for women in the second half of pregnancy. METHOD: A randomized, double-blind, placebo controlled trial. Thirty-one women received a daily dose of 27 mg elemental iron in a product containing both heme iron and non-heme iron (Hemofer), 30 women received the same dose as pure non-heme iron with vitamin C (Collets jern med vitamin C), and 29 women received placebo. A double dummy technique was used to mask tablets. The women were tested for red cell indices and iron status markers (s-ferritin, s-iron, Total Iron Binding Capacity and erythrocyte protoporphyrin) throughout pregnancy and 8 and 24 weeks postpartum. The results were analyzed according to the 'intention to treat' principle. RESULTS: The hematological effects were equal in the two treatment groups. 25% of the supplemented women fell below 110 g/l in Hb vs 52% in the placebo group (p < 0.05); none fell below 100 g/l in the supplemented groups, 14% in the placebo group. Iron status was significantly better for all measured parameters in the heme iron group compared to placebo at the end of pregnancy. Differences between the other groups were only shown for some parameters, probably due to the small sample size. In the heme iron group there were fewer women with empty iron stores postpartum than at the start of pregnancy (from 14% to 8%), in the non-heme iron group there was a significant increase (from 3% to 27%), and in the placebo group the percentage of women with empty iron stores was more than doubled (from 21% to 52%). CONCLUSIONS: A daily dose of 27 mg elemental iron, containing a heme component, given in the second half of pregnancy, prevents depletion of iron stores after birth in most women. An equivalent dose of pure inorganic iron seems less effective, but the sample size in this study was too small to demonstrate significant differences between the two treatment groups.

Effect of the microtubular inhibitor vinblastine on ferritin clearance and release in the rat.

We have previously demonstrated that colchicine inhibits ferritin clearance from the circulation of normal and iron-loaded rats and stimulates endogenous ferritin release into both the serum and bile of iron-loaded rats. The aim of the present study was to determine the effect of vinblastine on ferritin clearance and release in normal and iron-loaded rats. Vinblastine was administered at either 1 or 10 mg/kg to both normal and iron-loaded rats, infused over a 5 h period with either a rat liver ferritin or saline solution. Serum and biliary ferritin levels were determined every 30 min. After 5 h, 90% of the infused ferritin was cleared from the circulation in the absence of vinblastine. Low-dose vinblastine decreased ferritin uptake 10-20% in iron-loaded rats. High-dose vinblastine inhibited ferritin clearance by 25% in normal rats and 20-40% in iron-loaded rats. Vinblastine administration caused a 2-3-fold increase in the serum ferritin concentration and a 3-5-fold peak in biliary ferritin levels. Thus, vinblastine caused the release of endogenous ferritin into both the serum and bile of iron-loaded rats in the presence of a ferritin load. We therefore conclude that disturbed microtubule function accounts for the observed inhibition of ferritin uptake and intracellular transport; however, the mechanism of increased ferritin release remains unclear.

[Therapy and iron supplements with ferritin iron during pregnancy. Randomized prospective study of 458 cases]. / Terapia e supplemento marziale con ferro ferritinico durante la gravidanza. Studio prospettico randomizzato di 458 casi.

A randomized polycentric study was programmed to establish the effects of daily administration of ferritin iron from early pregnancy to puerperium. 254 women with normal iron balance at the beginning of their pregnancy were randomized receiving no supplements or 40 mg iron daily. At the end of pregnancy iron balance was still normal only in one third of the pregnant women of the first group versus two third of the second group. 204 women who were iron-deficient received daily 40 or 120 mg of iron; in this group anemia developed less frequently (13% versus 29%) and iron balance normalized in one subject on four; the great majority of these women remained iron-deficient. Unwanted effects of minimal or mild relevance, and almost always sporadic were observed in 6.5% of cases and with the reduction or withdraw of the treatment in only 1.4% of cases. These results showed that daily administration of ferritin iron during pregnancy is effective and well tolerated; furthermore they suggest that the treatment must be done with at least 60 mg daily in women with normal iron balance and protracted also after the puerperium in iron deficient subjects.

Iron supplementation in female blood donors deferred by copper sulfate screening.

Female blood donors with low hematocrit levels detected by copper sulfate screening were selected randomly to receive either 75 mg of iron per day, as ferrous gluconate, or a calcium phosphate placebo. Their ferritin, serum iron, total iron-binding capacity, zinc protoporphyrin, and hemoglobin values, as well as their suitability to donate blood, were determined initially (Visit 1) and at four follow-up visits (Visits 2-5). By the second visit, the serum ferritin and iron values of donors receiving iron supplementation differed significantly from those of donors receiving placebo. By the fifth visit, a less marked but significant increase in hemoglobin had occurred in the iron group, but not in the placebo group. At no time was there a significant difference between the groups' suitability to donate blood, with each group donating at almost half of their visits. The authors conclude that iron supplementation at this dose level in deferred female blood donors improves their iron status and hemoglobin levels, but does not significantly increase their suitability to donate blood as compared with the suitability of placebo-treated donors.

Iron stores in pregnant Nigerians and their infants at term.

Serum ferritin and blood haemoglobin were evaluated as indices of iron status in 65 pregnant Nigerians and in the cord blood of their full-term infants. All the mothers had taken iron and folate supplementation throughout pregnancy. The mean gravidity was 3.3 +/- 2.0. The mean cord ferritin concentration of 135.9 micrograms/l (77.6-238.2 micrograms/l) was 3.6 times the maternal level of 38.1 micrograms/l (17.3-83.8 micrograms/l). Parity had no effect on the haemoglobin or serum ferritin concentrations of the mothers or those of their babies. Maternal haemoglobin or serum ferritin concentrations correlated significantly (P less than 0.01) with cord levels, in babies with mothers of parity greater than or equal to 5. Infants of mothers with low iron stores (less than 20 micrograms/l) had significantly lower serum ferritin concentrations than infants of iron-replete mothers, which suggests variation in amounts of iron received during intrauterine growth. In order to ensure adequate iron stores in newborn infants, continual use of supplementary oral iron should be encouraged in pregnant Nigerians.

Enhanced iron removal from liver parenchymal cells in experimental iron overload: liposome encapsulation of HBED and phenobarbital administration.

The effectiveness of N,N'-bis[2-hydroxybenzyl]-ethylene-diamine-N,N'-diacetic acid (HBED) in removing radioiron introduced into the parenchymal cells of mouse liver as 59Fe-ferritin has been investigated. The effectiveness of HBED, an iron chelator of low water solubility, has also been compared with that of desferrioxamine (DF), an iron chelator of high water solubility and currently in clinical use for treatment of transfusional iron overload. Using the 59Fe excretion as the measure of effectiveness of chelation therapy and a standardized single chelator dose of 25 mg/kg, we have found that: (1) a saline suspension of HBED, prepared by sonication and given intraperitoneally to mice, promotes a small but significant increase in excretion of radioiron compared to the untreated controls, whereas DF, in its free form, is ineffective; (2) HBED encapsulated in lipid bilayers of liposomes and given intravenously is superior to nonencapsulated HBED; (3) DF encapsulated in small unilamellar liposomes is ineffective in removing iron given in the form of ferritin; (4) administration of phenobarbital in drinking water, at a concentration of 1 g/liter, induces a 30%-55% increase of iron excretion from untreated control mice and also from mice given HBED either in liposome-encapsulated or nonencapsulated form. We have demonstrated that HBED is superior to DF for removal of storage iron from liver parenchymal cells and that liposomes are useful carriers for iron chelators of low water solubility.

The influence of route of vaccination on the systemic and local immune response in the pig.

The influence of the route of vaccination on the systemic and local immune response has been studied in the sow with ferritin antigen using three methods of vaccination: 1. intramuscular with Freund's complete adjuvant (FCA); 2. intramammary without FCA; 3. intramammary with FCA. Intramammary vaccination was found to be superior to intramuscular vaccination in producing both a local and systemic response. Folowing stimulation by either route, antibody activity was found in all immunoglobulin classes, the major amount of antibody activity in a body fluid correlating with the major immunoglobulin class in that fluid. Antibody production was increased in all immunoglobulin classes by using FCA. Vaccination of one gland resulted in antibody activity in the secretions of the other mammary glands.