Changes In Transferrin Saturation Research Articles

Efficacy of Vitamin C with Iron Supplementation in Iron Deficiency Anemia Patients: A Systematic Review and Meta-Analysis

Background Oral iron supplementation is one of the mainstays of treatment for iron deficiency anemia (IDA) but can be complicated by poor absorption. Vitamin C is hypothesized to increase the acidity of the GI tract and enhance the conversion of non-absorbable ferric iron (Fe 3+) to its absorbable ferrous (Fe 2+) state for improved absorption and is often prescribed with iron. However, whether vitamin C supplementation translates to clinically relevant differences, such as sufficient improvements in hemoglobin, remains unclear and a synthesis of available evidence is lacking. Therefore, the present systematic review and meta-analysis aims to compare oral iron with or without vitamin C supplementation in patients with IDA. Methods MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials were searched from database inception to July 2023 for randomized controlled trials (RCTs) and non-randomized studies (NRSs) that investigated the use of oral iron supplements with vitamin C compared to oral iron supplements only in patients with IDA. Title & abstract, full text review and data extraction were conducted independently and in duplicate. The primary outcome was the change in serum hemoglobin levels in g/dL. Secondary outcomes include change in serum ferritin, change in transferrin saturation, change in reticulocyte percentage, and incidence of adverse events including constipation, nausea/vomiting, GI upset and poor taste. The Mantel-Haenszel fixed effects model was utilized for the meta-analysis. The calculated effect sizes were represented by odds ratios (OR) and mean differences (MD) for binary endpoints and continuous endpoints, respectively, with 95% confidence intervals (CI). Results 2231 studies were retrieved from electronic databases. 12 RCTs and one prospective cohort study comprising 2240 patients were included. There was a small but statistically significant increase in serum hemoglobin level (MD 0.14 g/dL [95%CI 0.08, 0.20]) and serum ferritin levels (MD 3.23 µg/L [95%CI 1.63, 4.84]) in the iron + vitamin C group compared to the iron only group. There was a greater reduction in serum transferrin saturation associated with vitamin C supplementation (MD -2.01% [95%CI -3.31, -0.71%]) but the pool of evidence consists of only two studies. Reticulocyte percentage (MD 0.22% [95%CI 0.08, 0.36]) was higher in the iron + vitamin C group than in the iron only group. There were no significant differences between the iron + vitamin C group and the iron only group in overall incidence of adverse effects (OR 0.71 [95%CI 0.50, 1.00]), constipation (odds ratio (OR) 0.83 [95%CI 0.35, 1.96]), or nausea/vomiting (OR 0.80 [95%CI 0.52, 1.24]). The risk of GI upset is lower in the iron + vitamin C group (OR 0.40 [95%CI 0.18, 0.92]). Nevertheless, only three primary studies reported on incidence of adverse events. Conclusion The addition of vitamin C to iron supplementation in the management of IDA was associated with a statistically significant, but likely clinically unimportant, increase in serum hemoglobin of 0.14 g/dL. Similarly, a statistically significant increase in serum ferritin levels by 3.23 µg/L was observed, but its clinical relevance remains uncertain. A strength of the present analysis is the number of RCTs included; however, its conclusions are limited by the heterogeneity of interventions (e.g. different formulations/dosage) across studies. Our results do not provide strong evidence for adding vitamin C to iron supplementation.

Possible Association of Energy Availability with Transferrin Saturation and Serum Iron during Summer Camp in Male Collegiate Rugby Players.

Low energy availability (LEA) may persist in rugby players. However, timely assessment of energy balance is important but is difficult. Therefore, a practical index that reflects energy availability (EA) is essential. A total of 19 male college rugby players participated in a 2-week pre-season summer camp. Their blood sample was collected after overnight fast prior to (Pre), in the middle (Middle), and after (Post) the camp. Their physical activity in the first half of the camp was calculated using the additive factor method in the forwards (FW; numbers 1–8) and backs (BK; numbers 9–15). The participants were categorized as tight five (T5; numbers 1–5), back row (BR; numbers 6–8), and BK for analysis. All the participants lost weight during the camp (range: from −5.9% to −0.1%). Energy balance in the first half of the camp was negative. Transferrin saturation (TSAT) and serum iron levels significantly decreased to half, or even less, compared with the Pre levels at week 1 and remained low. The changes in TSAT and serum iron levels exhibited a significant positive correlation with the changes in body weight (R = 0.720; R = 0.627) and with energy intake (R = 0.410; R = 461) in T5. LEA occurs in rugby summer camp but is difficult to assess using weight change. Alternately, TSAT and serum iron levels after overnight fast may be better predictors of LEA.

SO050DIFFERENT FERRIC CITRATE DOSE REGIMENS IN THE TREATMENT OF IRON DEFICIENCY ANAEMIA IN PATIENTS WITH NON-DIALYSIS-DEPENDENT CKD: THE COMPASS TRIAL

Abstract Background and Aims Ferric citrate (FC) is approved in the US as oral iron replacement for the treatment of iron deficiency anaemia (IDA) in adult patients with non-dialysis dependent (NDD) chronic kidney disease (CKD) and for the treatment of hyperphosphatemia in adult patients with dialysis dependent CKD. For IDA, a starting dose FC of 1 tablet three times daily (TID) is recommended with titration to maintain haemoglobin (Hb) at goal. This study was designed to investigate the possibility of dosing FC twice daily (BID) for flexibility in clinical practice. The efficacy and safety of different FC dosing regimens for the treatment of IDA were examined in adults with NDD-CKD. Method In this 48-wk, Phase 4, randomized, open-label, multicentre study, subjects with IDA of NDD-CKD (stage 3-5) were randomized 1:1 to receive 1 FC tablet (1gm containing 210mg ferric iron) TID or 2 tablets BID. At wk 12, subjects whose Hb increased <0.5 g/dL from baseline (BL) or was <10 g/dL had their dose increased to either 2 tablets TID or 3 tablets BID consistent with their original dosing regimen. This prespecified analysis reports data through wk 24. The primary endpoint was mean change in Hb from BL to wk 24. Secondary endpoints included mean change in transferrin saturation (TSAT), ferritin, and phosphate to wk 24. Results 206 subjects were randomized, 183 were included in this analysis after completing the 24-wk dose titration period. Groups were well matched with mean age of 69.5 +/- 10.32 years, 64% female and 54% had diabetes as a cause of CKD. Mean BL eGFR was 33.6 +/- 10.85 ml/min/1.73m2 and Hb 10.45 +/-0.744 g/dL. In subjects who did not require an increase in the FC dose at wk 12, mean changes in Hb at wk 24 were 1.05 and 1.24 g/dL in the 1 tablet TID and 2 tablet BID dosage groups, respectively. In subjects who required an increase in the FC dose at wk 12, mean changes in Hb at wk 24 were 0.41 and 0.13 g/dL in the 2 tablet TID and 3 tablet BID groups, respectively. Mean changes in TSAT, ferritin and phosphate are presented in the Table. The incidence of TEAEs was 78.2% and 75.0% in the BID and TID groups, respectively. The most common AEs reported were diarrhoea, stool discoloration and constipation. The incidence of SAEs was 13.9% and 17.3% in the BID and TID groups, respectively. Five deaths were reported, none were deemed related to FC per the investigator. Conclusion FC was effective and generally well tolerated in the treatment of IDA in this NDD-CKD population. Subjects who had per protocol FC dose increases at wk 12 had less pronounced iron deficiency at BL and smaller increases in Hb suggesting an additional underlying cause of anaemia. Mean changes in Hb, TSAT, ferritin, and phosphate and AE profiles were similar in the BID and TID regimens as well as in 3 g/day and 4 g/day dosing groups supporting the potential for dosing flexibility with FC. Clinicaltrials.gov identifier NCT03236246 Funding provided by Akebia Therapeutics, Inc.

Canagliflozin Improves Erythropoiesis in Diabetes Patients with Anemia of Chronic Kidney Disease.

Background: We evaluated the erythropoietic effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes patients with anemia of chronic kidney disease.Methods: Nine diabetes patients were enrolled and administered 100 mg canagliflozin once a day for 12 weeks. The patients received fixed doses of conventional antidiabetic drugs and renin-angiotensin system inhibitors for 8 weeks before enrollment; these drugs were continued during the study. Endpoints were changes in erythropoiesis parameters, including erythrocyte and reticulocyte count, hemoglobin, hematocrit, and serum erythropoietin (EPO) concentration from baseline to 12 weeks. All variables were measured every 2 weeks.Results: Serum EPO concentration increased by 38 [15–62]% (P = 0.043) between baseline and 2 and 4 weeks. Reticulocyte count transiently increased at 2 weeks. Erythropoiesis occurred after 2 weeks of canagliflozin treatment. Erythrocyte count (from 386 ± 36 × 104/μL to 421 ± 36 × 104/μL; P = 0.0009), hemoglobin (from 11.8 ± 0.6 g/dL to 12.9 ± 1.1 g/dL; P = 0.0049), and hematocrit (from 37.1 ± 2.3% to 40.4 ± 3.2%; P = 0.002) increased from baseline to study completion. Although there were no significant changes in transferrin saturation, serum ferritin levels were decreased (P = 0.003).Conclusions: Canagliflozin treatment led to an improvement in erythropoiesis in patients with impaired kidney function. The effect on erythropoiesis appeared to be due to an EPO production-mediated mechanism and might be independent of glycemic control; however, further studies are needed to clarify this since the present study had a small sample size and no comparator group.

The Ferumoxytol for Anemia of CKD Trial (FACT)\u2014a randomized controlled trial of repeated doses of ferumoxytol or iron sucrose in patients on hemodialysis: background and rationale

BackgroundIron deficiency anemia (IDA) is a common manifestation of chronic kidney disease (CKD), affecting most patients on hemodialysis and imposing a substantial clinical burden. Treatment with iron supplementation increases hemoglobin levels and can reduce the severity of anemia in patients with CKD. While correcting anemia in these patients is an important therapeutic goal, there is a lack of long-term trials directly comparing intravenous iron therapies in patients with CKD receiving hemodialysis.Methods/DesignThe Ferumoxytol for Anemia of CKD Trial (FACT) is a 13-month, open-label, randomized, multicenter, international, prospective study with 2 substudies. Entry criteria for the main study include adults with IDA (defined as hemoglobin <11.5 g/dL [<115.0 g/L] and a transferrin saturation <30%), serum ferritin <800 ng/mL (<1798 pmol/L), and receiving hemodialysis for ≥3 months. Patients are randomized to receive ferumoxytol (1.02 g over 2 doses) or iron sucrose (1.0 g over 10 doses) during the initial 5-week treatment period. Those with persistent/recurrent IDA over the 11-month observation period will receive additional 5-week treatment periods, as appropriate. The primary efficacy endpoint of the main study is the mean change in hemoglobin from Baseline to Week 5 for each treatment period. The secondary efficacy endpoints include the mean change in transferrin saturation from Baseline to Week 5 and the proportion of patients with a hemoglobin increase of ≥1.0 g/dL at any time from Baseline to Week 5. Safety will be assessed through an examination of the adverse event profile over the course of the study. An “oxidative stress” substudy in approximately 100 patients will assess the effects of treatment on biomarkers of oxidative stress/inflammation during the initial 5-week treatment period, and a magnetic resonance imaging substudy in approximately 70 patients will assess the potential for iron deposition in target tissues over 24 months.DiscussionFACT fulfills the need for a long-term comparative trial in patients with IDA and CKD receiving hemodialysis. The efficacy and safety results will provide useful information for guiding therapy in this population. Two hundred ninety-six patients have been enrolled, and completion of the main study is expected soon.Trial registrationClinicalTrials.gov identifier: NCT01227616 (registered October 22, 2010); EudraCT number: 2010-022133-28

Ferumoxytol versus placebo in iron deficiency anemia: efficacy, safety, and quality of life in patients with gastrointestinal disorders.

IntroductionIron deficiency anemia (IDA) is common in patients with gastrointestinal (GI) disorders and can adversely affect quality of life. Oral iron is poorly tolerated in many patients with GI disorders. Ferumoxytol is approved for the intravenous treatment of IDA in patients with chronic kidney disease. This study aimed to evaluate the efficacy and safety of ferumoxytol in patients with IDA and concomitant GI disorders.Patients and methodsThis analysis included 231 patients with IDA and GI disorders from a Phase III, randomized, double-blind, placebo-controlled trial evaluating ferumoxytol (510 mg ×2) versus placebo in patients who had failed or were intolerant of oral iron therapy. The primary study end point was the proportion of patients achieving a ≥20 g/L increase in hemoglobin (Hgb) from baseline to Week 5. Other end points included mean change in Hgb, proportion of patients achieving Hgb ≥120 g/L, mean change in transferrin saturation, and patient-reported outcomes (PROs).ResultsSignificantly more patients with IDA receiving ferumoxytol achieved a ≥20 g/L increase in Hgb versus placebo (82.1% vs 1.7%, respectively; P<0.001). Mean increase in Hgb (28.0 g/L vs −1.0 g/L, respectively; P<0.001) significantly favored ferumoxytol treatment. Ferumoxytol-treated patients demonstrated significantly greater improvements than placebo-treated patients relative to their very poor baseline PRO scores posttreatment, including improvements in the Functional Assessment of Chronic Illness Therapy–Fatigue questionnaire and various domains of the 36-Item Short-Form Health Survey. Ferumoxytol-treated patients had a low rate of adverse events.ConclusionIn this study, ferumoxytol was shown to be an efficacious and generally well-tolerated treatment option for patients with IDA and underlying GI disorders who were unable to use or had a history of unsatisfactory oral iron therapy.

Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD.

Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders.

A Randomized, Open-Label, Non-Inferiority Study of Intravenous Iron Isomaltoside 1,000 (Monofer) Compared With Oral Iron for Treatment of Anemia in IBD (PROCEED)

OBJECTIVES:In the largest head-to-head comparison between an oral and an intravenous (IV) iron compound in patients with inflammatory bowel disease (IBD) so far, we strived to determine whether IV iron isomaltoside 1,000 is non-inferior to oral iron sulfate in the treatment of iron deficiency anemia (IDA).METHODS:This prospective, randomized, comparative, open-label, non-inferiority study was conducted at 36 sites in Europe and India. Patients with known intolerance to oral iron were excluded. A total of 338 IBD patients in clinical remission or with mild disease, a hemoglobin (Hb) <12 g/dl, and a transferrin saturation (TSAT) <20% were randomized 2:1 to receive either IV iron isomaltoside 1,000 according to the Ganzoni formula (225 patients) or oral iron sulfate 200 mg daily (equivalent to 200 mg elemental iron; 113 patients). An interactive web response system method was used to randomize the eligible patient to the treatment groups. The primary end point was change in Hb from baseline to week 8. Iron isomaltoside 1,000 and iron sulfate was compared by a non-inferiority assessment with a margin of −0.5 g/dl. The secondary end points, which tested for superiority, included change in Hb from baseline to weeks 2 and 4, change in s-ferritin, and TSAT to week 8, number of patients who discontinued study because of lack of response or intolerance of investigational drugs, change in total quality of life (QoL) score to weeks 4 and 8, and safety. Exploratory analyses included a responder analysis (proportion of patients with an increase in Hb ≥2 g/dl after 8 weeks), the effect of regional differences and total iron dose level, and other potential predictors of the treatment response.RESULTS:Non-inferiority in change of Hb to week 8 could not be demonstrated. There was a trend for oral iron sulfate being more effective in increasing Hb than iron isomaltoside 1,000. The estimated treatment effect was −0.37 (95% confidence interval (CI): −0.80, 0.06) with P=0.09 in the full analysis set (N=327) and −0.45 (95% CI: −0.88, −0.03) with P=0.04 in the per protocol analysis set (N=299). In patients treated with IV iron isomaltoside 1,000, the mean change in s-ferritin concentration was higher with an estimated treatment effect of 48.7 (95% CI: 18.6, 78.8) with P=0.002, whereas the mean change in TSAT was lower with an estimated treatment effect of −4.4 (95% CI: −7.4, −1.4) with P=0.005, compared with patients treated with oral iron. No differences in changes of QoL were observed. The safety profile was similar between the groups. The proportion of responders with Hb ≥2 g/dl (IV group: 67% oral group: 61%) were comparable between the groups (P=0.32). Iron isomaltoside 1,000 was more efficacious with higher cumulative doses of >1,000 mg IV. Significant predictors of Hb response to IV iron treatment were baseline Hb and C-reactive protein (CRP).CONCLUSIONS:We could not demonstrate non-inferiority of IV iron isomaltoside 1,000 compared with oral iron in this study. Based on the dose–response relationship observed with the IV iron compound, we suggest that the true iron demand of IV iron was underestimated by the Ganzoni formula in our study. Alternative calculations including Hb and CRP should be explored to gauge iron stores in patients with IBD.

The Evaluation of Long-Term Ferumoxytol Use as An Iron Replacement Therapy In Patients with Iron Deficiency Anemia

AbstractAbstract 5156 BACKGROUND:Iron deficiency anemia (IDA) is the most common cause of anemia worldwide. The World Health Organization (WHO) estimates that as many as 1.6 billion people worldwide (25% of the world's population) have IDA, and the National Center for Health Statistics estimates that 3.4 million people in the US have IDA. Various underlying conditions have been linked to IDA, which in industrialized nations primarily include chronic kidney disease (CKD), menstrual and postpartum blood loss, pregnancy, gastrointestinal (GI) blood loss, and cancer. Regardless of underlying cause, iron replacement therapy is essential for increasing iron stores and raising hemoglobin levels in patients with IDA. Typically, one gram of iron is the standard IV iron therapeutic dose for the management of IDA. Ferumoxytol is approved in the US for the treatment of IDA in adult subjects with CKD and is marketed under the trade name Feraheme® (ferumoxytol) Injection. Ferumoxytol is administered as two IV injections of 510 mg (17 mL) 3 to 8 days apart, for a total cumulative dose of 1.02 g. METHODS:To provide a convenient, safe, and effective method for increasing iron in patients with IDA and a history of unsatisfactory oral iron therapy, AMAG is undertaking a global Phase III clinical development program. This program includes a randomized, double-blind, placebo-controlled trial in 800 subjects (ClinicalTrials.gov NCT01114139) followed by a sixth-month, open-label extension trial (ClinicalTrials.gov NCT01114217). The primary objective of the double-blind placebo-controlled study is to evaluate the efficacy and safety of a 1.02 g course of IV ferumoxytol, administered as two doses of 510 mg each, compared with placebo (normal saline). This trial will randomize subjects to ferumoxytol or placebo at a ratio of 3:1. Subjects will have a variety of underlying conditions including ongoing abnormal uterine bleeding (AUB), GI disorders (eg, inflammatory bowel disease, gastric bypass), cancer, postpartum blood loss, and other conditions such as nutritional iron deficiency, heart failure, and rheumatoid arthritis. Following study completion (a 5-week treatment period) all subjects will have an opportunity to enroll into the extension trial (NCT01114217), which will evaluate the safety and efficacy of ferumoxytol for the episodic treatment of IDA over a 6-month period. In both trials, key efficacy endpoints will be based on evaluations of hemoglobin through 5 weeks following treatment with ferumoxytol. Additional assessments will include change in transferrin saturation, and the impact of ferumoxytol treatment on both the use of erythropoiesis stimulating agents and the need for blood transfusions. Both of these trials will also include patient reported outcomes to assess the impact of IV iron therapy on anemia symptoms and health-related quality of life (fatigue, energy). Additionally, detailed information on healthcare utilization will be collected. CONCLUSION:In addition to providing efficacy, safety, and patient reported outcome information on the administration of ferumoxytol for the treatment of IDA in a broad patient population, these trials (NCT01114139 and NCT01114217) will contribute novel data regarding the requirement for repeat therapy with IV iron and the safety and efficacy of long-term repeat use of IV iron in the treatment of IDA. Disclosures:Poma:AMAG Pharmaceuticals, Inc.: Employment. Diana:AMAG Pharmaceuticals, Inc.: Employment. McLaughlin:AMAG Pharmaceuticals, Inc.: Employment. Kausz:AMAG Pharmaceuticals, Inc.: Employment.

Deferasirox induces regression of iron overload in patients with myelodysplastic syndromes

Transfusion-related morbidity is an emerging problem in chronically transfused patients with myelodysplastic syndromes (MDS). Although several iron-chelating drugs are available, the optimal way of treatment of iron-overload remains uncertain. A major disadvantage of deferoxamine is that the drug has to be applied as continuous subcutaneous infusion. Therefore, novel oral agents have been developed. One of these drugs is deferasirox (Exjade). We report on 14 MDS patients who were treated with deferasirox (500-1500 mg daily) for up to 24 months. In these patients, treatment responses were recorded by determining serum ferritin levels before and during therapy and by applying recently established response criteria. In all patients except one, ferritin levels decreased during therapy. Four patients showed a complete response, one a minor response and five a stable iron load. In the responding patients, initially elevated liver enzymes decreased substantially. No substantial change in transferrin saturation or transfusion frequency was recorded. Side effects were mild and tolerable in most patients. In one patient, treatment with deferasirox was stopped because of impaired kidney function. Our data show that treatment with deferasirox is a reasonable approach to counteract iron overload in patients with MDS.

Hemojuvelin: a supposed role in iron metabolism one year after its discovery

The discovery of hemojuvelin and its association with juvenile hemochromatosis are important not only for the diagnostics of this rare severe disease but also for the understanding of the complex mechanism of iron metabolism regulation. Currently, the physiological role of hemojuvelin is obscure. Recent experimental and clinical studies indicate that hemojuvelin will probably be a regulator of hepcidin, similar to HFE and transferrin receptor 2. However, in contrast to transferrin receptor 2, which is relevant in the hepcidin response to changes in transferrin saturation, HFE and especially hemojuvelin seem to be involved in the inflammation-induced hepcidin expression. Hepcidin, generally accepted as a hormone targeting enterocytes and macrophages, decreases iron absorption from the intestinal lumen and iron release from phagocytes. This mechanism explains the central role of hepcidin and, indirectly, its regulator, hemojuvelin, in the pathogenesis of hemochromatosis but also in anemia of chronic disease. Further basic and clinical research is needed to uncover the details of hemojuvelin pathophysiology required for potential pharmacological interventions.

Milk Fortif Ed with Iron Or Iron Supplementation to Improve Nutritional Status of Pregnant Women: An Intervention Trial from Rural Vietnam

Anemia is still the major nutritional problem among pregnant women in Southeast Asia. The objective of this study was to measure hemoglobin status and reduction of underweight in a group of pregnant women who received iron-fortified or nonfortified milk, and another group who received iron supplements (tablets) or placebo. The 44 women in the iron-fortified milk group received 15 mg of iron per day per 400 ml of milk, and 41 women received placebo. The 40 women in the iron supplement group received 60 mg of iron per day, and 43 women received nonfortified milk. During this intervention trial, all women were supervised from the 14th to the 18th week of gestation until delivery. Blood was sampled at 0, 5, 10, and 16 weeks of intervention. After the 16th week of intervention, the changes in hemoglobin (deltaHb) concentrations in both treatment groups (the iron-fortified milk and the iron tablet groups) were not significantly different (deltaHb: -0.5+/-0.9 and -0.3+/-0.9 g/L, respectively), but the changes were significantly greater in the nonfortified milk and placebo groups (deltaHb: -1.2+/-0.9 and -1.1+/-0.8 g/L, respectively; p < .01). The change in transferrin saturation (deltaTS) in the iron-fortified milk group (deltaTS: 3.4+/-12.9%) was greater than that in the placebo and nonfortified milk groups (deltaTS: -10.1+/-9.8% and -11.6+/-10.7 %, respectively) (p < .01). The weight gain of the subjects during intervention did not differ significantly in the fortified and nonfortified milk groups (delta weight: 5.0+/-2.0 and 5.8+/-2.1 kg, respectively), but was higher than in the iron tablet group (delta weight: 4.6+/-3.1 kg; p < .05) and the placebo group (delta weight: 3.8+/-2.5 kg; p < .001). Iron supplementation and fortification were seen to be effective in promoting weight gain in pregnant Vietnamese women. For women who are underweight, the administration of iron-fortified milk has additional benefits to those of supplementation, most likely due to additional energy and nutrient inputs.

Changes in transferrin saturation after treatment with the oral iron chelator deferiprone in patients with iron overload.

To evaluate the changes in transferrin saturation in patients with iron overload following the oral administration of the iron chelator deferiprone; to assess the correlation between the degree of transferrin desaturation, the deferiprone dose, and urinary iron excretion. Serum samples were obtained from 16 patients with iron overload at different time intervals following the oral administration of deferiprone (50 mg/kg). These samples were analysed using 6M urea/polyacrylamide gel electrophoresis (UPAGE). This method is able to resolve serum transferrin into four different forms (free iron, two forms of monoferric, and diferric). The deferiprone concentration in these samples was estimated using high pressure liquid chromatography (HPLC). Zero time samples (t0) from 10 patients were incubated with 150 microM deferiprone or normal saline either at room temperature or at 37 degrees C for 30 minutes and 24 hours, and also at -20 degrees C for six weeks. Samples were then analysed using UPAGE. A maximum decrease in transferrin saturation from (mean (SD)) 93.0 (10.6)% to 54.5 (17.2)% was observed 72.5 (50.0) minutes after deferiprone administration and in most of the patients coincided with peak deferiprone concentration. This was associated with a maximum rise in the percentage of iron free transferrin (apotransferrin) from 2.9 (7.0)% to 27.3 (17.8)%. The total amount of iron estimated to be removed from transferrin constituted 21.3 (20.2)% of the 24 hour urinary iron excretion measured during the study. When deferiprone (150 mumol/l) was incubated in vitro with t0 samples from 10 patients for 30 minutes and 24 hours at room temperature, 37 degrees C, and at -20 degrees C for six weeks, deferiprone was more efficient at removing iron from transferrin at 37 degrees C, with maximum transferrin desaturation accomplished within 30 minutes compared with 24 hours at room temperature. The results confirm that deferiprone can remove iron from transferrin when administered orally to patients with iron overload and that transferrin bound iron may, therefore, be a significant source of the iron chelated by deferiprone in vivo.

Developmental changes in plasma transferrin concentrations related to red cell ferritin.

Transferrin, the plasma iron transport protein, has two iron-binding sites but is usually only partly saturated. (Essentially all plasma iron is bound to transferrin.) Thus, changes in transferrin saturation reflect differences in the concentrations of plasma iron and/or transferrin. Developmental changes in red cell ferritin content coincide with a 2.5 times increase in plasma transferrin and a proportional decrease in saturation, in the bullfrog model system. The possible relationship of the degree of transferrin saturation and structure on the distribution of iron between heme and ferritin was examined in suspensions of reticulocytes, which synthesize both ferritin and heme. The extra transferrin in adult plasma was indistinguishable from transferrin in tadpole plasma in terms of the ability to donate iron to red cell heme and ferritin in vitro and in terms of surface charge (pI 6.55, 6.34), molecular weight (73,000), carbohydrate content (2%), amino acid composition, and immunological reactivity. Only the saturation in vivo appeared to differ. When the saturation of transferrin was manipulated in vitro, an effect on the relative distribution of iron between heme and ferritin was observed. The heme-synthesizing system consumed a disproportionately large amount of the delivered iron until it was saturated, a point which coincided with transferrin saturation; as the degree of transferrin saturation decreases, iron delivered to red cell iron stores (ferritin) decreases disproportionately. Thus, the developmental increase in plasma transferrin and consequent decrease in saturation minimize the amount of iron available for storage in red cells. The effect is further enhanced by the decreased ability of adult erythrocytes to incorporate iron from transferrin, a property which may be related to quantitative changes observed in iodination of a Mr = 168,000 membrane protein.

Iron

Although a majority of disorders of iron nutrition are a result of iron deficiency, a small but clinically significant group of conditions is characterized by an overload of iron. Iron status must be assessed through a number of tests. The serum ferritin concentration reflects the size of iron stores, and changes in transferrin saturation and red cell protoporphyrin indicate alterations in iron supply.

Effect of transferrin saturation on iron delivery in rats.

Studies were carried out in rats to evaluate the release of iron from monoferric and diferric transferrin. Isoelectric focusing was carried out on plasma tagged at low and high saturations, and it was shown that these represented primarily monoferric and diferric transferrin, respectively. In vivo studies with these tagged plasmas were carried out on normal, iron-deficient, and hypertransfused rats. In all three groups there was a greater in vivo uptake of iron from diferric transferrin by all tissues monitored. Though the amount varied in different animals, the ratio of uptake between diferric and monoferric transferrin iron varied between 1.56 and 2.10 in the erythron and between 2.38 and 2.65 in the liver. These studies indicate that changes in transferrin saturation, by changing the proportion of monoferric to diferric transferrin iron, changed the amount of iron released to tissues.