Total Body Iron Content Research Articles

Evaluation of dietary composition between hemoglobin categories, total body iron content and adherence to multi-micronutrients in preschooler residents of the highlands of Puno, Peru

BackgroundThe anemia prevalence is higher in highlands populations. It is assumed that iron deficiency anemia (IDA) in children is mainly due to low dietary intake. However, other suggest that high prevalence of anemia is due to an inappropriate hemoglobin (Hb) adjustment for altitude.Materials and methodsCross-sectional study conducted in 338 preschoolers (PSC) from Puno-Peru. Hb was measured in whole blood, and ferritin, Soluble transferrin receptor, and Interleukin 6 in serum.The dietary iron intake was assessed by 24-h dietary recall, using NutriCap Software. Hb concentration was assessed as adjusted or unadjusted for altitude.ResultsWith unadjusted Hb, the anemia prevalence was 4.7%, whereas after Hb correction, the prevalence raised-up to 65.6% (p < 0.001). Reciprocally, erythrocytosis proportion decreased from 20.35 to 0.30% (p < 0.001). Total Body Iron (TBI) showed that 7.44% had ID and 0.32% had IDA. PSC with normal unadjusted Hb levels have more protein and micronutrients intake than anemic ones. PSC with erythrocytosis consumed less fat, and more niacin and ascorbic acid than anemics. Total iron intake was lower in anemic than the other groups, but without statistical significance due to the standard deviation of the data in a small number of anemic PSC (n = 16). TBI, unadjusted Hb, and adjusted Hb were not different between groups consuming or not multimicronutrients.ConclusionsThe consumption of iron and iron status in children who live at high altitude is adequate, and that anemia could be due to other micronutrient deficiencies and/or that the adjustment of Hb by altitude is inappropriate.

Splenic iron decreases without change in volume or liver parameters during luspatercept therapy

AbstractSplenic iron decreased whereas liver iron was stable during luspatercept therapy in some individuals with thalassemia. This suggests a reduction of ineffective erythropoiesis changes the organ distribution of iron and demonstrates that liver iron concentration alone may not accurately reflect total body iron content. This article describes data from subjects enrolled in BELIEVE (NCT02604433) and BEYOND (NCT03342404).

Hepcidin and Iron in Health and Disease.

Hepcidin, the iron-regulatory hormone, determines plasma iron concentrations and total body iron content. Hepcidin, secreted by hepatocytes, functions by controlling the activity of the cellular iron exporter ferroportin, which delivers iron to plasma from intestinal iron absorption and from iron stores. Hepcidin concentration in plasma is increased by iron loading and inflammation and is suppressed by erythropoietic stimulation and during pregnancy. Hepcidin deficiency causes iron overload in hemochromatosis and anemias with ineffective erythropoiesis. Hepcidin excess causes iron-restrictive anemias including anemia of inflammation. The development of hepcidin diagnostics and therapeutic agonists and antagonists should improve the treatment of iron disorders.

Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis.

Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.

Dose Effect of Bovine Lactoferrin Fortification on Iron Metabolism of Anemic Infants.

To evaluate the effect of iron-fortified formula with different concentrations of bovine lactoferrin (bLF) on improvement of anemic status in term infants who were previously breast-fed. A randomized, controlled, open, and post-market intervention study. A total of 108 infants aged 6-9 mo who were previously breast-fed and weaned were selected. The subjects were divided into three groups with the sequence of outpatient: fortified group 1 (FG1) with a bLF concentration of 38 mg/100 g, FG2 with 76 mg/100 g bLF, FG0 with no bLF. The intervention duration was 3 mo. Weight, height, head circumference and the concentration of hemoglobin (Hb), serum ferritin (SF), serum transferring receptor (sTfR) were measured and sTfR-SF index (TFR-F index) and total body iron content (TBIC) were computed before and after intervention. The primary outcome measures were obtained from 96 infants (35, 33 and 28 for FG0, FG1 and FG2, respectively). After 1 mo of intervention, the changes of Hb level showed no significant difference (p>0.05) among the three groups, however, the Hb level of infants in FG2 were significantly higher than those of infants in the other two groups after 3 mo of intervention (p<0.05). The present data indicated that the formula fortified with 76 mg/100 g bLF positively affected the Hb of anemic infants who were previously breastfed when compared with fortification with 38 mg/100 g bLF and no bLF fortification.

Cardiovascular evaluation and management of iron overload cardiomyopathy in sickle cell disease

Cardiovascular evaluation and management of iron overload cardiomyopathy in sickle cell disease

Iron-Deficiency Anaemia-From the Prospect of Community Health Nursing

Anaemia is the worldwide major public health problem. Globally, there are around two billion anemic people and approximately 50% of them are suffering from iron deficiency anaemia, which is one of the most common nutritional anaemia. Iron deficiency anaemia can be defined as the condition in which the total body iron content is decreased below a normal level that affects hemoglobin synthesis. A number of factors such as poor dietary intake, iron malabsorption, excessive blood loss, pregnancy, child birth, chronic inflammations and infections may contribute to iron deficiency anaemia. It is characterized by headache, difficulty in concentration, fatigue, weakness, palpitations, breathlessness, dyspnea, pallor skin and mucous membranes, smooth or sore tongue etc. If anaemia is not diagnosed and treated at an early stage, it may have severe health consequences that hamper the nation's social and economic development. This review article throws the light on Anaemia, its risk factors, clinical manifestations, diagnosis, WHO cut-off points and their adjustment according to altitude and smoking habits, interventions in national health programmes and the role of the community health nurse in prevention and control of iron-deficiency Anaemia.

Iron metabolism in infants: influence of bovine lactoferrin from iron-fortified formula

ObjectiveThe aim of this study was to evaluate whether an iron-fortified formula with a concentration of lactoferrin would significantly improve the hematologic indexes and iron status in term infants compared with those same values in infants fed an iron-fortified formula without lactoferrin. MethodIn this prospective, multicenter, controlled intervention study, 260 infants ages 4 to 6 mo were selected from six maternal and children's health care hospitals in the area. All infants were divided into two groups with the sequence of outpatient: lactoferrin-fortified formula milk group (fortified group, FG, containing lactoferrin 38 mg/100 g milk and iron element 4 mg/100 g milk) and no lactoferrin fortified milk (control group, CG, containing lactoferrin 0 mg/100 g milk and iron element 4 mg/100 g milk) for 3 mo. The levels of weight, height, and head circumference and the concentration of hemoglobin (Hb), serum ferritin (SF), and serum transferring receptor (sTfR) were measured and sTfR-SF index (TFR-F index), total body iron content (TBIC) and low height for age (HAZ), low weight for age (WAZ), and low weight for height (WHZ) were computed before and after the intervention, respectively. ResultsIn all, 213 (115 in FG and 98 in CG) infants completed the intervention trial and all measurements of biochemical indicators. There were no significant differences in the average amount of daily intake of formula milk (94.3 ± 9.8 g versus 88.2 ± 8.7 g for FG and CG; P > 0.05) and iron element (3.8 ± 0.4 mg versus 3.7 ± 0.6 mg for FG and CG; P > 0.05). The average amount of daily intake of lactoferrin for infants in FG group was 35.8 ± 3.7 mg. The levels of weight, WAZ, WHZ, Hb, SF, TFR-F index, and TBIC after intervention of infants in FG were all significantly higher than those of infants in CG weight, 8723 ± 245 g versus 8558 ± 214g; WAZ, 1.02 ± 0.31 versus 0.44 ± 0.18; WHZ, 0.98 ± 0.31 versus 0.41 ± 0.12; Hb, 125.5 ± 15.4 g/L versus 116.9 ± 13.1 g/L; SF, 44.7 ± 17.2 μg/L versus 31.6 ± 18.4 μg/L; TFR-F index, 1.88 ± 0.41 versus 1.26 ± 0.39; TBIC, 6.12 ± 0.78 mg/kg versus 5.26 ± 0.55 mg/kg for FG and CG; P < 0.05), but significantly lower (P < 0.05) for the prevalence of anemia (4.1% versus 7.5%), iron deficiency (13.9% versus 24.4%), and iron-deficient anemia (1.7% versus 6.1%). ConclusionWhen infants who were exclusively breastfed were supplemented with lactoferrin-fortified milk, significant increases in TBIC and iron absorption in the intestine were seen.

Effect of vitamin A supplements on iron metabolic homeostasis for preschoolers

To explore the effect of vitamin A (VA) combined iron supplements on iron metabolic homeostasis for preschoolers. About 445 preschoolers with aged 3-6 years old from eight kindergartens in Pixian county, Chengdu were recruited into this trial from March to September, 2011. All subjects met the inclusion criteria were randomly divided into four groups using random number table: sole VA supplementation group (VA group, a single oral dose of VA at about 200 000 units), sole iron supplementation group (FE group, daily oral supplementation with the element iron 1-2 mg·kg(-1)·d(-1) for five days a week, lasting for 6 months), the combined supplementation of VA and iron group (VF group) and control group (CO group, no VA and iron supplementation). The concentration of serum VA, serum ferritin (SF), serum transferring receptor (sTfR), C-reactive protein (CRP) and hemoglobin (Hb) were measured from 3 ml vein blood. The sTfR-SF index (TFR-F index) and total body iron content (TBIC) before and after intervention were calculated. The differences of these indexes between groups before and after intervention were analyzed. The level of sTfR before intervention in VA group ((1.78 ± 0.17) mg/L) was significantly higher than that of after intervention ((1.18 ± 0.11)mg/L) (t = 28.88, P < 0.01). The levels of TFR-F index and TBIC in FE and VF groups before intervention ( (1.59 ± 0.37), (1.63 ± 0.40) and (9.04 ± 2.71), (9.26 ± 2.33) mg/kg, respectively) were all lower than those of after intervention (TFR-F index:(1.84 ± 0.51), (1.87 ± 0.45) and TBIC:(12.42 ± 3.49), (13.01 ± 2.98)mg/kg) (t values were 3.93, 3.78, 7.57 and 9.41, respectively, all P values were <0.01). The incidence of iron deficiency in VA, FE, and VF groups before intervention were 26% (25/95), 31% (30/98) and 31% (28/90) and were 41% (39/95), 10% (10/98) and 18% (16/90) for after intervention, respectively. The difference of this index in VA, FE and VF groups were significant (χ(2) values were 4.59, 12.50 and 4.31, respectively, all the P values were <0.05). Combined VA and iron was as effective as VA alone or iron alone in decreasing the iron deficiency, the impact of VA intervention on iron metabolic homeostasis was mainly manifested in iron usage and mobilization, but showed no effect on total body iron content.

No enhancing effect of vitamin A administration on iron absorption or body total iron content in preschool children from Chengdu, China.

To explore the effect of vitamin A supplements on iron metabolic homeostasis for preschoolers. This was a randomized, placebo-controlled and blinded intervention trial with 3- to 6-y old preschoolers. A total of 445 subjects were randomly divided into four groups: a vitamin A supplementation group (group 1, a single oral dose of vitamin A as retinol 200,000 IU), an iron supplement group (group 2, daily oral supplement with the elemental iron 1-2 mg/kg/d for 5 d a week, lasting for 6 mo) a combined vitamin A and iron (group 3) and administration of no vitamin A or iron as a placebo-control (group 4). A total of 387 (95, 98, 90 and 104 from groups 1, 2, 3 and 4) children completed the intervention. After intervention, serum retinol levels of children in group 1 and group 3 was markedly higher than those of children in groups 2 and 4 (p<0.05). The serum ferritin level of children in group 1 significantly decreased after intervention (p<0.05), but increased in group 2 (p<0.05). The sTfR-SF index (TFR-F) and total body iron content (BTIC) showed the same change after intervention. In group 2 and group 3, the levels of TRF-F index and BTIC had statistically increased to the same degree after intervention (p<0.05). The impact of vitamin A intervention on iron metabolic homeostasis was mainly manifested in storage and mobilization; there was no direct effect on total body iron content or iron absorption in the intestine.

Systemic Iron Homeostasis

The iron hormone hepcidin and its receptor and cellular iron exporter ferroportin control the major fluxes of iron into blood plasma: intestinal iron absorption, the delivery of recycled iron from macrophages, and the release of stored iron from hepatocytes. Because iron losses are comparatively very small, iron absorption and its regulation by hepcidin and ferroportin determine total body iron content. Hepcidin is in turn feedback-regulated by plasma iron concentration and iron stores, and negatively regulated by the activity of erythrocyte precursors, the dominant consumers of iron. Hepcidin and ferroportin also play a role in host defense and inflammation, and hepcidin synthesis is induced by inflammatory signals including interleukin-6 and activin B. This review summarizes and discusses recent progress in molecular characterization of systemic iron homeostasis and its disorders, and identifies areas for further investigation.

Results from a 1-year, open-label, single arm, multi-center trial evaluating the efficacy and safety of oral Deferasirox in patients diagnosed with low and int-1 risk myelodysplastic syndrome (MDS) and transfusion-dependent iron overload

The majority of patients with myelodysplastic syndrome (MDS) present with anemia and will become dependent on regular transfusions of packed red blood cells (PRBC) with the risk of iron overload (IOL). Liver iron content best reflects the total body iron content, and measurement of liver iron concentration (LIC) by MRI is a validated tool for detection, but data in MDS is rather limited. Here we present the results of a multi-center trial evaluating the efficacy and safety of deferasirox (DFX) in low and intermediate-1 risk MDS patients with transfusion-dependent IOL. Three patients with transfusion frequency of > 4 units PRBC per month were initially treated with 30mg/kg/day while in 46 patients with a lower transfusion burden deferasirox was initiated at 20mg/kg/day, due to patient related reasons one patient received DFX in a dose of 6mg/kg/day only. LIC was measured by MRI at baseline and end of study using the method by St. Pierre et al. The intention to treat population consisted of 50 MDS patients (28 male; 22 female) with a median age of 69years who were treated with DFX for a median duration of 354days. Mean daily dose of DFX was 19mg/kg/day. Median serum ferritin level (SF) at baseline was 2,447ng/mL and decreased to 1,685ng/mL (reduction by 31%) at end of study (p = 0.01). In 7 (13%) patients the initially chosen dose had to be increased due to unsatisfactory efficacy of chelation therapy. For 21 patients, LIC measurement by liver MRI was performed at baseline and for 19 of these patients at the end of study: mean LIC decreased significantly from 16,8mg/g dry tissue weight (± 8.3mg/g dry tissue weight) at study entry to 10,8mg/g dry tissue weight (± 10.4mg/g dry tissue weight) at end of study (p = 0.01). Of all patients exposed to the study drug (n = 54), 28 (52%) did not complete the 12month study period most commonly due to AEs in 28% (n = 15) and abnormal laboratory values in 7% (n = 4), respectively. The most common adverse events (≥ 10% of all patients) with suspected drug relationship were diarrhea (n = 25, 46%), nausea (n = 13, 24%), upper abdominal pain (n = 8, 15%), serum creatinine increase (n = 16, 30%) and rash (n = 5, 9%). Adverse events making dose adjustments or interruption of study drug necessary occurred in 33 patients (61%). Hematologic improvement according to IWG criteria (2006) was observed in 6 patients (11%). Initiation of treatment of IOL with DFX depending on the transfusion burden yields sufficient reduction of excess iron indicated by serum ferritin levels and most importantly by liver MRI. The safety profile of DFX was comparable to previous observations.

A rare cause of osteonecrosis

IntroductionHereditary hemochromatosis (HH) is an autosomal recessive disorder caused by mutations in the HFE gene, which increase intestinal iron absorption. The prevalence of C282Y homozygosity, which causes the disorder, is 0.5% in Caucasian populations. The clinical manifestations are related to excess iron in the tissues, especially the liver, heart, pancreas, pituitary, and skin. They include fatigue, loss of libido or impotence in males, liver disease, skin pigmentation, diabetes mellitus, cardiac enlargement—with or without heart failure, and conduction defects. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation (“bronze diabetes”) results from a combination of iron deposits and melanin. It occurs late in the disease, when the total body iron content is more than five times the normal value, about 20 grams. Left untreated, approximately half of all patients with HH eventually develop arthralgia or arthropathy. Chondrocalcinosis, chronic pseudo-osteoarthritis, and osteoporosis are the major rheumatic manifestations of HH. The cause of the arthropathy is still unknown. Iron deposits within joints may trigger a number of pathologic events, such as free radical generation and crystal deposition, which stimulate immune complex formation and inflammation.Materials and methodsWe describe the case of a 48-year-old male suffering from chronic bilateral ankle pain.ResultsThe work-up revealed osteonecrosis of ankle. The patient also presented high plasma ferritin levels and homozygosity for the C282Y mutation. Other than HH, which was confirmed by liver biopsy, the patient had no other risk factors for osteonecrosis.DiscussionHH represents a rare cause of osteonecrosis, and there are no prior reports of aseptic osteonecrosis of the ankle in a patient with this disease. The pathogenetic mechanism remains unknown.

Effects of vitamin A, vitamin A plus iron and multiple micronutrient-fortified seasoning powder on iron metabolic homeostasis

To evaluate the effect of vitamin A, vitamin A plus iron and "7 + 1" multiple micronutrient-fortified seasoning powder on iron metabolic homeostasis in preschool children. This was a randomized, controlled and blinded interventional field trial. A total of 226 2 - 7 years old preschool children were recruited from three nurseries in the area, and they were randomly assigned into three different fortified diet groups for 6 months. The subjects in Group I were fortified with vitamin A; those in Group II and III were fortified with vitamin A plus iron and vitamin A plus iron, thiamine, riboflavin, folic acid, niacinamide, zinc and calcium (7 + 1), respectively. The concentration of serum vitamin A was measured by high-performance liquid chromatography (HPLC), serum ferritin (SF) was measured by enzyme-linked immunosorbent assay (ELISA), soluble transferrin receptor (sTfR) was measured by microparticle-enhanced, and hemoglobin (HB) by hemiglobincyanide, the sTfR-SF index (TFR-F index) and total body iron content were computed respectively before and after intervention. Simultaneously, children's demographic data, socio-economic status and eating habits, etc. were investigated by questionnaires. A total of 226 preschool children were included in the study with age ranged from 2 to 7 years with average age (4.0 ± 0.85) (means ± standard deviation). The prevalence of anemia, deficient iron storage, vitamin A deficiency (VAD) and suspect sub-clinical vitamin A deficiency (SSVAD) were 23.5%, 15.0%, 6.3% and 25.9%, respectively. The levels of SF and sTfR significantly decreased after intervention in all groups (χ(2) = 8.3298, χ(2) = 16.1471, χ(2) = 15.1371, χ(2) = 15.1171, χ(2) = 5.2617, χ(2) = 4.8844, P < 0.05) especially in group II and group III for SF (χ(2) = 16.1471, χ(2) = 15.1371, P < 0.05) and group I for sTfR (χ(2) = 15.1171, P < 0.05). No marked change of TFR-F index and total body iron contents was observed in group I (t = 0.1817, t = 1.7736, P > 0.05), while TFR-F index decreased and total body iron contents increased in group II and group III (t = 5.3561, t = 6.5979, t = 11.1663, t = 8.7306, P < 0.05) after intervention. Vitamin A intervention has significant effect on iron storage and mobilization but seldom effect on iron absorption in small intestine. The combination of vitamin A and other micronutrients might be a better intervention for the improvement of iron deficiency for preschool-children.

Una rara causa di osteonecrosi

Summary Introduction Hereditary hemochromatosis (HH) is an autosomal recessive disorder caused by mutations in the HFE gene, which increase intestinal iron absorption. The prevalence of C282Y homozygosity, which causes the disorder, is 0.5% in Caucasian populations. The clinical manifestations are related to excess iron in the tissues, especially the liver, heart, pancreas, pituitary, and skin. They include fatigue, loss of libido or impotence in males, liver disease, skin pigmentation, diabetes mellitus, cardiac enlargement—with or without heart failure, and conduction defects. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation (“bronze diabetes”) results from a combination of iron deposits and melanin. It occurs late in the disease, when the total body iron content is more than five times the normal value, about 20 grams. Left untreated, approximately half of all patients with HH eventually develop arthralgia or arthropathy. Chondrocalcinosis, chronic pseudo-osteoarthritis, and osteoporosis are the major rheumatic manifestations of HH. The cause of the arthropathy is still unknown. Iron deposits within joints may trigger a number of pathologic events, such as free radical generation and crystal deposition, which stimulate immune complex formation and inflammation. Materials and methods We describe the case of a 48-year-old male suffering from chronic bilateral ankle pain. Results The work-up revealed osteonecrosis of ankle. The patient also presented high plasma ferritin levels and homozygosity for the C282Y mutation. Other than HH, which was confirmed by liver biopsy, the patient had no other risk factors for osteonecrosis. Discussion HH represents a rare cause of osteonecrosis, and there are no prior reports of aseptic osteonecrosis of the ankle in a patient with this disease. The pathogenetic mechanism remains unknown.

Evidence for evolutionary constraints in Drosophila metal biology

Mutations in single Drosophila melanogaster genes can alter total body metal accumulation. We therefore asked whether evolutionary constraints maintain biologically abundant metal ions (iron, copper, manganese and zinc) to similar concentrations in different species of Drosophilidae, or whether metal homeostasis is a highly adaptable trait as shown previously for triglyceride and glycogen storage. To avoid dietary influences, only species able to grow and reproduce on a standard laboratory medium were selected for analysis. Flame atomic absorption spectrometry was used to determine metal content in 5-days-old adult flies. Overall, the data suggest that the metallome of the nine species tested is well conserved. Meaningful average values for the Drosophilidae family are presented. Few statistically significant differences were noted for copper, manganese and zinc between species. In contrast, Drosophila erecta and Drosophila virilis showed a 50% increase above average and a 30% decrease below average in iron concentrations, respectively. The changes in total body iron content correlated with altered iron storage in intestinal ferritin stores of these species. Hence, the variability in iron content could be accounted for by a corresponding adaptation in iron storage regulation. We suggest that the relative expression of the multitude of metalloenzymes and other metal-binding proteins remains overall similar between species and likely determines relative metal abundances in the organism. The availability of a complete and annotated genome sequence of different Drosophila species presents opportunities to study the evolution of metal homeostasis in closely related organisms that have evolved separately for millions or dozens of million years.

Brain iron homeostasis and neurodegenerative disease

AD= : Alzheimer disease; APP= : amyloid precursor protein; ATP= : adenosine triphosphate; BBB= : blood–brain barrier; DMT1= : divalent metal transporter-1; FA= : Friedreich ataxia; FTL= : ferritin light chain; FTH= : ferritin heavy chain; NBIA= : neurodegeneration with brain iron accumulation; NTBI= : non–transferrin-bound iron; PANK2= : pantothenate kinase 2; PD= : Parkinson disease; PKAN= : pantothenate kinase–associated neurodegeneration; TfR1= : transferrin receptor 1. Iron is essential for multiple functions in the CNS, including DNA synthesis, gene expression, myelination, neurotransmission, and mitochondrial electron transport. Several proteins implicated in brain iron homeostasis are involved in disorders associated with abnormal iron metabolism. A basic understanding of mechanisms of iron homeostasis is of clinical relevance, as either accumulation or depletion of intracellular iron may impair normal function and promote cell death. Iron accumulates in selective brain regions during aging, in acquired neurodegenerative disorders such as Alzheimer disease (AD) and Parkinson disease (PD), and in genetic disorders such as neurodegeneration with brain iron accumulation (NBIA). Dysregulation of iron homeostasis is also a critical feature of Friedreich ataxia (FA). The link between iron and neurodegenerative disease provides potential therapeutic targets for these disorders. Brain iron metabolism and its implications in neurodegeneration have been the subjects of excellent reviews.1–6 Some general concepts, unresolved issues, and clinical correlations are briefly discussed here. The CNS is separated from the systemic circulation by the blood–brain barrier (BBB), a tight epithelial barrier analogous to that of the mammalian duodenum, which is the site of absorption of dietary iron. After absorption, iron in its oxidized (ferric) form binds to serum transferrin and is distributed throughout the general circulation. The presence of a BBB explains the relative independence of the brain iron from the total body iron content. This is reflected by the absence of brain iron overload in mouse models and in humans with hemochromatosis due to mutations of the HFE gene, encoding a protein that regulates iron absorption.1,2 ### Incorporation and transport of iron in the nervous system. Iron incorporation and transport in the brain depends on interactions between the endothelial cells and astrocytes (figure). Brain endothelial cells express the transferrin receptor 1 (TfR1) in their luminal membrane; this receptor binds iron-loaded transferrin and internalizes this complex in endosomes. Within the endosomes, …

T2* MRI Provides No Evidence for Myocardial and Pancreatic Iron Overload in Multitransfused Patients with Sickle/β-Thalassemia.

Introduction: Transfusion-dependent hemolytic anemias particularly thalassemia major (thal.m) and also sickle cell disease (SCD) result in iron deposition in the reticuloendothelial system in major organs, mainly in the liver and also in the heart and endocrine glands. However, liver iron levels in patients with thal.m measured by other techniques were found to have no predictive values for the extent of their cardiac iron deposition. T2* MRI sequences have been previously addressed as a reliable tool for non invasive evaluation of iron load in the liver, heart and pancreas. Patients with T2* value > 20 ms have normal cardiac function while the prevalence of myocardial dysfunction and arrhythmias increases as a consequence of cardiac iron overload (T2* < 20 ms). A previous study comparing cardiac iron overload in transfusion dependent thal.m and SCD patients matched for age and liver iron content, found abnormally low cardiac T2* values (<20 ms) in nearly 40% of patients with thal.m, while the T2* values were normal in the patients with SCD (1) (Blood : 103;1934, 2004). The purpose of the present study was to quantify iron content (T2* values) in the liver, heart and pancreas of multitransfused patients with sickle/β-thal.Patients and Methods: Eleven patients with sickle/β-thal., 3 males and 8 females, mean age 31 years ± 9.5 (SD) were analyzed, 6 of them were splenectomized. Their mean ± SD values for hemoglobin was 9.0 gr/dl, for serum ferritin - 3900 ng/ml ± 3944 and for transferrin saturation - 80% ± 23. All of them were transfused and received a mean of 97 packed cell units ± 88 (SD). Only one patient received iron chelation for 10 months until 6 months prior to entering the study. Seven patients received regularly Hydrea 1–1.5 gr/day for > 10 years. MRI evaluation (1.5T, GE MRI system) included: Left ventricular (LV) function (ejection fraction)- steady-state free procession (SSFP) cine sequence as well as iron load quantification- breath-hold multi echo gradient echo T2*, sampled across regions of interest in the LV septum, liver parenchyma and pancreatic tissue. (Eur. Heart J 22:2171, 2001)Results: All patients had normal T2* values in the heart (>20ms) and in the pancreas (>30ms). The left ventricular ejection fraction, left ventricular endsystolic and endiastolic volumes (evaluated both by echo-cardiography and by cine function MRI) were normal in all patients. There was no evidence for pleural or pericardial effusion. The diameter of the pulmonary artery and right ventricle were normal. Seven patients demonstrated evidence of mild to moderate iron deposition in the liver (T2* <6.3 ms). In these patients mean serum ferritin (5656 ng/ml) and transferrin saturation (92.4%) were significantly higher (p=0.001) than in 4 patients with normal T2* levels in the liver (>6.3ms) where mean serum ferritin was 872ng/ml and transferrin saturation 59.5%.Conclusion: The T2* MRI values of 11 patients with sickle/β-thal. showed that whereas 7 patients had a certain degree of iron deposition in the liver, none demonstrated cardiac or pancreatic iron deposition. Therefore, with respect to iron deposition, multitransfused patients with sickle/β-thal. are similar to patients with homozygous SCD and not to patients with thal.m and thal intermedia. The reasons for this observation are still unclear. This similarity could be related in part to the relativly low number of transfusions, starting later in life, of patients with homozygous SCD or sickle/β- thal. compared to patients with thal.m. (1) The liver is the dominant iron storage organ and iron liver concentration correlates closely with the total body iron content. While iron uptake by hepatocytes is predominately mediated via transferrin and correlates with serum ferritin levels, as confirmed in the present study, this is not the case in regulation of cardiac and endocrine iron uptake. These organs might acquire the excess metal differently. It is possible that additional and/or different forms of iron, which have been identified, such as non-transferrin bound iron and labile plasma iron, are involved in determining iron loading in the heart and endocrine glands and/or because regulation of iron entry into the plasma by hepcidin might differ. Additional studies are in progress to address these issues.

Ineffective Erythropoiesis in β-Thalassemia Is Characterized by Increased Iron Absorption Mediated by down Regulation of Hepcidin and up Regulation of Ferroportin.

Progressive iron overload occurs in β-thalassemia as a result of increased gastrointestinal absorption. Our goal is to investigate the relationship between ineffective erythropoiesis (IE), iron-related genes and organ iron distribution in mice that exhibit levels of anemia consistent with thalassemia intermedia (th3/+) and major (th3/th3), as we described previously. The th3/th3 mice die in 8 weeks due to severe anemia but can be rescued by transfusion therapy. We analyzed up to 90 animals at 2, 5 and 12 months, as appropriate. We monitored various hematological parameters, tissue iron content and quantitative-PCR levels of Hamp, Fpn1, Smad4, Cebpa, Hfe, Tfr1 and other genes involved in iron metabolism in liver, spleen, kidney, heart and duodenum. At 2 months, th3/th3 mice had the highest total body iron content and highest degree of IE. The total iron was 53.6±21.0, 406.1±156.1, 657.7±40.3 μg in the spleen, and 107.5±35.7, 208.5±24.9 and 1298.7±427.5 μg in the liver of +/+, th3/+ and th3/th3, respectively (n≥5 per genotype). However, if the organ size was not taken in account, the iron concentration in the spleen of th3/+ was higher, in average, than that of th3/th3 mice (3.8±1.5 and 2.9±0.5 μg/mg), while in the liver was the opposite (0.6±0.1 and 5.1±2.0 μg/mg of dry weight, P<0.001). Heme and non-heme iron analyses provided similar results. Surprisingly, the distribution of iron within organs also differed. In th3/+ mice, the hepatic iron was almost exclusively located in Kupffer cells, whereas in th3/th3 mice in parenchymal cells. Our data suggest that Hamp is responsible for the increased iron absorption, being reduced to 20% and 70% in 2 month-old th3/+ and th3/th3 mice compared to +/+ animals (P<0.001). Hfe was reduced by 50% (P<0.05) in the liver of the animals that expressed low Hamp levels, indicating that Hfe could be directly responsible for Hamp regulation or share the same regulatory pathway. Low levels of Smad4 and Cebpa were observed only in the liver of mice with the lowest Hamp expression (P<0.05), indicating that these proteins might contribute to further decreased Hamp synthesis. In addition, while Tfr1 in th3/+ mice was 40% lower in the liver, it was up-regulated (400%) in th3/th3 mice (P<0.001), which may explain why iron is increased more in the liver of th3/th3 mice. In 5 and 12 month-old th3/+ mice, the surprising observation was the normal expression level of Hamp. However, in the duodenum, the Fpn1 RNA and protein levels were augmented (300%, P<0.001). In transfused th3/+ and th3/th3 animals, Hamp, Hfe, Cbpa and Smad4 expression levels were normalized or increased, while Tfr1 was down-regulated in both groups, which may explain the increased splenic iron deposition in these animals. Our data suggest that IE, together with the relative expression levels of Hamp and Tfr1, is largely responsible for the organ iron overload observed in young thalassemic mice. However, in older mice, it is the increase of Fpn1 levels in the duodenum that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the genesis of iron overload in β-thalassemia.

Diagnostic work-up of iron deficiency / Diagnostisches Vorgehen bei Eisenmangel

Abstract Abstract Iron deficiency (ID) is defined as a diminished total body iron content. Three degrees of severity have been defined: storage iron depletion (stage I), iron-deficient erythropoiesis (stage II), and iron deficiency anemia (stage III). When assessing the patient’s iron status, it is important to bear in mind that each of the various iron tests indicate something different in terms of ID. As they detect different stages of ID, the parameters efficiently complement each other to characterize the iron status in the individual patient. Of particular clinical interest are newer iron tests of the iron-deficient erythropoiesis: zinc protoporphyrin (ZPP), soluble transferrin receptor (sTfR), hypochrome erythrocytes (Hypo) and reticulocyte hemoglobin (CHr). Supervising the final step of the heme production, ZPP can be used as a reliable and inexpensive screening test of the whole iron metabolism. sTfR measurement is a useful tool to distinguish between real iron deficiency and functional iron deficiency in anemia of chronic disorders. Hypo and CHr seem to be the best parameters to diagnose ID in hemodialysis patients treated with recombinant human erythropoietin.