Preoperative use of parenteral iron
•Download as PPT, PDF•
15 likes•5,547 views
This is a comprehensive review of the physiology and pathophysiology of iron deficiency anemia and the evolution of its treatment with parenteral iron to the current recommendations. In our practice, in an attempt to minimize allogenic blood transfusions, we optimize preoperatively patients with iron deficiency anemia by means if intravenous iron replacement.
![[object Object],Disclosure of Financial Relationships](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
Recommended
More Related Content
What's hot
What's hot (20)
Viewers also liked
Viewers also liked (12)
Similar to Preoperative use of parenteral iron
Similar to Preoperative use of parenteral iron (20)
More from MedPeds Hospitalist
More from MedPeds Hospitalist (9)
Recently uploaded
Recently uploaded (20)
Preoperative use of parenteral iron
- 1. Perioperative Management of Iron Deficiency Anemia Moises Auron MD FAAP, FACP Hospital Medicine
- 5. Muñoz M. Vox Sanguinis. 2008; 94: 172–183 Regulation of Iron Metabolism
- 6. Erythropoiesis in CKD Kalantar-Zadeh K. Adv Chron Kid Dis. 2009; 16(2): 143-151.
- 10. Tests to assess Iron deficiency Muñoz M. Vox Sanguinis. 2008; 94: 172–183
- 11. Serum Transferrin Receptor (sTfR) Skikne BS. Am J Hematol. 2008; 83:872–875.
- 12. Indian J Pediatr 2010; 77 (2) : 179-183
- 14. Degree of Iron deficiency Gasche C, et al. Inflamm Bowel Dis 2007;13:1545–1553
- 15. Mortality predictability in CKD Kalantar-Zadeh K. Adv Chron Kid Dis. 2009; 16(2): 143-151.
- 20. Algorithm for IV Iron replacement Muñoz M. Vox Sanguinis. 2008; 94: 172–183
- 23. Parenteral Iron Gasche C, et al. Inflamm Bowel Dis 2007;13:1545–1553. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022180lbl.pdf Name Molecular Anaphylaxis Test dose [Fe] Max Weight (kD) required (mg/ml) Dose Dextran - HMW (Dexferrum®) 265 Y Y 50 1g - LMW (Infed®) 165 Y Y 50 1g Fe gluconate (Ferrlecit®) < 50 N N 12.5 125mg Fe sucrose (Venofer®) 30-100 N N 20 200mg
- 32. IV Iron in Non-dialysis CKD MacDougall IC. Curr Med Res & Opin. 2010; 26(2):473–482.
- 35. Auerbach M. Am J Hematol. 2008; 83: 580–588
- 41. Iron and infectious diseases Weinberg ED. Emerg Infect Dis 1999;5:346—52.
- 42. Body iron and disease Weinberg ED. Emerg Infect Dis 1999;5:346—52.
Editor's Notes
- Fig. 1 Main pathways of iron absorption, distribution and storage in humans. Keys. 1. Ferrireductase; 2. Divalent metal transporter (DMT-1); 3. Haem receptor; 4. Haem hydroxilase; 5. Ferroportin (Fpn1); 6. Haefastin; 7. Transferrin receptor-1 (TfR1); 8. Natural resistance macrophage protein (Nramp-2); 9. Transferrin receptor-2 (TfR2); 10. Ceruloplasmin; 11. Others: bacteria, lactoferrin, Hb-haptoglobin, Haem-haemopexin, etc. 12. Others: Hb, haem, ferritin. Most iron is recycled from the breakdown of old red blood cells by macrophages of the reticuloendothelial system. Circulating iron is bound to transferrin This chelation renders the iron soluble and prevents iron-mediated free radical toxicity. The mechanism by which transferrin acquires iron from intestinal absorptive cells and reticuloendothelial cells is unknown. Iron homeostasis is regulated strictly at the level of intestinal absorption and release of iron from macrophages. Intestinal iron absorption - daily diet contains ~ 15 mg of heme iron. 30 % is absorbed, likely via its own transport system. (heme carrier protein 1, has been found in the apical brush border membrane of duodenal enterocytes in the mouse). Molecular mechanisms of intestinal heme absorption are unclear. A heme carrier protein has been proposed, which is highly expressed in the gut and stimulated by hypoxia Heme dietary sources (fish, poultry, and meat) have a higher bioavailability (30%) than do non-heme (vegetable) sources (10 %). Absorption is affected by intraluminal factors: Ascorbic acid enhances the absorption of non-animal sources of iron such as cereal, breads, fruits, and vegetables Tannates (teas), bran foods rich in phosphates, and phytates inhibit iron absorption Iron in food is prominently ferric (Fe3+), which is poorly soluble above a pH of 3 and is therefore poorly absorbed. Ferrous iron (Fe2+) is more soluble, even at the pH of seven to eight seen in the duodenum. As a result, it is more easily absorbed. Ferrous iron is taken up at the mucosal side by the intestinal transporter. Duodenal cytochrome b provides reduction of ferric to ferrous iron. Inracellularly iron is transported to the basolateral portion of the cell by cytosolic low molecular weight iron carriers. Then a duodenal iron exporter, ferroportin releases iron from the cell; where it is oxidized to the ferric form (by hephaestin, a ceruloplasmin homologue, a ferrooxidase), and loaded onto transferrin. Regulation of iron absorption The rate of iron absorption is appropriately enhanced when iron stores are reduced or absent. Iron absorption is increased when there is increased erythropoiesis, especially in disorders that cause ineffective erythropoiesis (beta thalassemia, sideroblastic anemia, or variants of the myelodysplastic syndrome) Iron loss Iron is lost in sweat, shed skin cells, and perhaps some gastrointestinal loss at a rate of approximately 1 mg/day. A normal adult Western male has 1 to 2 mg of heme iron and 10 to 15 mg of other iron in his diet. If 30 percent of the heme iron and 10 percent of the other iron is absorbed, then the total rate of iron absorption is 1 to 2 mg/day This explains gender differences in the size of iron stores (men have stable turnover). Iron release from macrophages ~ 20 to 25 mg of iron are released daily from the breakdown of senescent red cells in the macrophages. Hemoglobin heme released from phagocytosed red cells is catabolized by microsomal heme oxygenase to biliverdin and carbon monoxide and the resulting free iron is released to the circulation through ferroportin or stored in ferritin according to the body needs and to the local concentration of hepcidin. Hepcidin coordinates both duodenal iron absorption as well as macrophage iron release.
- INTRODUCTION — The study of hemoglobins, both normal and mutant, has provided fundamental insights into structure-function relationships of proteins in general and, in particular, the molecular basis of oxygen transport. The discovery that sickle hemoglobin has an abnormal electrophoretic mobility began the era of molecular medicine [ 1 ]. With the advent of recombinant DNA technology, research on hemoglobin provided early and important information about the organization and regulation of genes as well as insights as to how ontogeny affects gene expression [ 2 ]. Hemoglobin motifs can be found in the most ancient unicellular plants and animals and have evolved over hundreds of millions of years into gas transport proteins through the processes of gene duplication, conversion, divergence, and inactivating mutation that have culminated in hemoglobin gene clusters on separate chromosomes, whose expression is developmentally-regulated [ 3 ]. All human hemoglobin genes contain 3 exons separated by 2 introns; the exons may encode distinct functional domains of the molecule. The tetrameric globular structure of hemoglobin lends is adapted to the physiology of complex organisms and their needs for regulation of oxygen delivery far better than primitive globins like hemocyanin or erythrocruorin, and single chain globins like muscle myoglobin or the other cellular globins such as cytoglobin and neuroglobin. The primary amino acid structure of the constituent globin chains dictates the quaternary structure, which, in turn, is the basis of the ability of hemoglobin to rapidly bind oxygen in the lungs and unload it in the tissues. Hemoglobin function may be altered by mutation, pH, and 2,3-biphosphoglycerate (2,3-BPG, also called 2,3-diphosphoglycerate or 2,3-DPG). STRUCTURE — Hemoglobin is a 64.4 kd tetramer consisting of two pairs of globin polypeptide chains: one pair of alpha-like chains, and one pair of non-alpha chains. The chains are designated by Greek letters, which are used to describe the particular hemoglobin (eg, Hb A is alpha2/beta2). Two copies of the alpha-globin gene (HBA2, HBA1) are located on chromosome 16 ( figure 1 ) along with the embryonic zeta genes (HBZ). There is no substitute for alpha globin in the formation of any of the normal hemoglobins (Hb) following birth (eg, Hb A, Hb A2, and Hb F). Thus, absence any alpha globin, as seen when all 4 alpha-globin genes are inactive or deleted is incompatible with extrauterine life, except when extraordinary measures are taken. A homotetramer of only alpha-globin chains is not thought to occur, but in the absence of alpha chains, beta and gamma homotetramers (HbH and Bart's hemoglobin, respectively) can be found, although they lack cooperativity and function poorly in oxygen transport. The single beta-globin gene (HBB) resides on chromosome 11, within a gene cluster consisting of an embryonic beta-like gene, the epsilon gene (HBE1), the duplicated and nearly identical fetal, or gamma globin genes (HBG2, HBG1), and the poorly expressed delta-globin gene (HBD) ( figure 1 ). A heme group, consisting of a single molecule of protoporphyrin IX coordinately bound to a single ferrous (Fe2+) ion, is linked covalently at a specific site to each globin chain. If the iron is oxidized to the ferric state (Fe3+), the protein is called methemoglobin. Alpha globin chains contain 141 amino acids (residues) while the beta-like chains contain 146 amino acids. Approximately 75 percent of hemoglobin is in the form of an alpha helix. The nonhelical stretches permit folding of the polypeptide upon itself. Individual residues can be assigned to one of eight helices (A-H) or to adjacent nonhelical stretches. Heme iron is linked covalently to a histidine at the eighth residue of the F helix (His F8), at residue 87 of the alpha chain and residue 92 of the beta chain. Residues that have charged side groups, such as lysine, arginine, and glutamic acid , lie on the surface of the molecule in contact with the surrounding water solvent. Exposure of the hydrophilic (charged) amino acids to the aqueous milieu is an important determinant of the solubility of hemoglobin within the red blood cell and of the prevention of precipitation. The hemoglobin tetramer is a globular molecule (5.0 x 5.4 x 6.4 nm) with a single axis of symmetry [ 4 ]. The polypeptide chains are folded such that the four heme groups lie in clefts on the surface of the molecule equidistant from one another. Oxygenation and deoxygenation — Oxygenation and deoxygenation of hemoglobin occur at the heme iron. Upon deoxygenation, the hemoglobin molecule undergoes a marked change in conformation, as the beta chains rotate apart by approximately 0.7 nm. Deoxyhemoglobin is stabilized in a constrained or tense (T) configuration by inter- and intra-subunit salt bonds. These salt bonds are responsible for the Bohr effect and for the binding of 2,3-BPG, both of which modify oxygen affinity (see below). Upon the addition of oxygen, the salt bonds are sequentially broken and the fully oxygenated hemoglobin is in the relaxed (R) configuration. In this state, there is less bonding energy between the subunits and the oxygenated molecule is able to dissociate reversibly, forming two alpha-beta dimers. It is these dimers that are bound to haptoglobin and can be filtered at the glomerulus. Each subunit in the tetramer is oriented toward the two unlike subunits in different ways (ie, alpha1/beta1 and alpha1/beta2). There is stronger binding between alpha1 and beta1 subunits than between alpha1 and beta2 subunits; as a result, dissociation of the oxygenated tetramer into dimers occurs at the alpha1/beta2 interface. During oxygenation and deoxygenation, there is considerable movement along the alpha1/beta2 interface. Hemoglobin mutants with an amino acid substitution at this interface are likely to have markedly abnormal functional properties
- Diagnostic indicators of iron deficiency anemia Intuitively, combining several iron status indicators provides the best assessment of iron status. Serum transferrin receptor and serum transferrin receptor log/ferritin index sTfR reflects erythropoiesis and inversely the amount of iron available for erythropoiesis. Values of sTfR are elevated in IDA due to the upregulation of synthesis of transferrin receptors on the erythrocytes so the cells can compete for iron more efficiently. Unlike serum ferritin, sTfR concentrations are not affected by the presence of inflammation [2]. The ratio between sTfR and serum ferritin concentrations, or sTfR–F index, is also considered a good indicator for evaluation of iron deficiency. sTfRs can contribute significantly to the detection of IDA; however, some claim it to be not any better than serum ferritin [3–7]. Yang et al. [8] compared the plasma ferritin concentrations alone with the sTfR–F ratio in infants, school-aged children and pregnant women measuring plasma ferritin, sTfR and C-reactive protein (CRP). They concluded that iron status can be effectively measured using plasma ferritin concentrations alone, provided a biomarker such as CRP is also measured to avoid falsely elevated plasma ferritin secondary to concurrent inflammation. Chang et al. [9] compared the utility of serum sTfR levels to bone marrow iron stores in identifying IDA. Bone marrow aspirates were performed in adult patients and hematologic assays: sTfR, serum ferritin, Hb, mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC). Cutoff values consistent with previous studies [10,11] that were used to exclude iron deficiency included ferritin values of at least 100 mcg/l and an sTfR/log ferritin ratio of more than 2.5. Elevated sTfR levels were found to be the most sensitive marker for the detection of absent bone marrow iron (100%), whereas the sTfR–F ratio of more than 2.5 had a lower sensitivity (50%). sTfR–F did have better sensitivity and specificity compared with the serum sTfR value alone when differentiating between IDA from ACD , which has been previously reported [2,10–13]. Goyal et al. [14] evaluated sTfR–F indices to determine the prevalence of ACD, and ACD with coexistent IDA in rheumatoid arthritis (RA) patients. The sTfR–F index was found to be a useful measure in classifying patients with ACD and coexistent IDA (80%) versus patients with pure ACD (20%). They also determined that sTfR–F index values of less than 2.2 mg/l excludes IDA, whereas values of more than 2.9 mg/l confirmed IDA . A similar study [15] compared the utility of serum ferritin, serum iron and bone marrow iron stores in diagnosing iron deficiency in RA outpatients. On the basis of the bone marrow iron stores, 36% of patients had IDA and 64% exhibited ACD. Correlation between the serum ferritin and the bone marrow iron stores was poor in the IDA group yet significant in the ACD group. Negative predictive values were highest when cutoff values for serum ferritin were less than 82 mcg/l in contrast to other studies’ cutoff values of 30–70mg/l [16,17]. Transferrin receptor — The gene for the TfR is also located on the long arm of chromosome 3. It codes for a homodimeric transmembrane protein (mol wt 94 kDa) that is found on most cells, but most densely on erythroid precursors and placental cells [ 10 ]. There is a binding site for the transcription factor Stat5 in the first intron of the TfR gene [ 11 ]. Expression of constitutively active Stat5A in an erythroid cell line increased TrF1 levels, while lethally irradiated mice that received a transplant of Stat5a/b (-/-) liver cells developed microcytic, hypochromic anemia. Each TfR molecule can bind two diferric Tf molecules (four Fe3+ atoms), which it endocytoses after clustering on clathrin coated pits. The iron is off loaded in acidified vacuoles and the apotransferrin-TfR complex is recycled to the cell surface where apo-Tf is discharged and released back into the circulation [ 10 ]. As occurs in other iron genes, TfR mRNA has a 3' IRE and is posttranscriptionally regulated by IRPs (see below). Inactivation of Tfr in mice is embryonically lethal due to severe anemia and abnormal central nervous system development. Haploinsufficiency of Tfr causes microcytosis and a reduction of total body iron [ 12 ]. Serum (soluble) TfR (sTfR) is a product of membrane TfR, which is released into the circulation by membrane proteases when TfR is not associated with its ligand, diferric transferrin, as occurs in iron deficiency [ 13 ]. Levels of sTfR measured in sera correlate directly with erythropoietic expansion. Transferrin receptor 2 — Transferrin receptor 2 (TfR2) is a member of the TfR family and is homologous to TfR1, but has no IRE elements and has a low affinity for transferrin [ 15 ]. It displays a restricted expression pattern, being present at high levels in hepatocytes. TfR2 may bind diferric transferrin and HFE [ 16,17 ] and is considered a sensor of Tf saturation Zinc protoporphyrin/heme ratio Evaluation of iron status using the ZPP/H is another diagnostic indicator of IDA diagnostic of early iron depletion [18]. The ZPP/H ratio reflects iron status in the bone marrow during the formation of Hb [19]. When iron supply is diminished, Zn utilization increases resulting in a high ZPP/H ratio. Das and Philip [20] compared the utility of ZPP/H ratio as a diagnostic measure of IDA with bone marrow iron store aspirates. In tandem with Hb and red blood cell indices, ZPP was reliable in reflecting the bone marrow iron status except in the prelatent phase of iron deficiency; however, it lacked the ability to distinguish between ACD and IDA. Using ZPP/H ratio to determine iron stores is preferential over the invasiveness of bone marrow aspiration. Others have reported that the ZPP/H ratio increase also compares favorably with serum ferritin concentration decrease, MCV and Hb levels in diagnosing IDA and preanemic iron depletion [19,21]. As zinc is also influenced by inflammation, ZPP interpretation can be challenging [22,23]. Reticulocyte hemoglobin content CHr assesses the amount of Hb in reticulocytes [24–27]. Measurement of CHr provides a snapshot of iron immediately available for erythropoiesis over the previous 3–4 days, making it functional as an early indicator of iron stores. BloodCHr has been found to be comparable to the traditional parameters for iron deficiency (serum iron, serum ferritin and Hb) for confirming the diagnosis of iron-deficient states [25–27,28]. Blood CHr has also been identified as an early indicator of the response to parenteral iron therapy, increasing within 2–4 days if sequential measurements are observed [28]. Endoscopy - Patients (50 years of age), with positive FOBT or positive family history for colonic cancer were invited to undergo a colonoscopy. Endoscopic evaluation revealed a likely cause of IDA in 68.5% of patients. The cause was due to iron malabsorption in 65.2% of patients, secondary to H. pylori pangastritis, celiac disease and atrophic gastritis. Only 3.7% of iron deficiency anemic patients exhibited bleeding lesions, whereas 67.4% were diagnosed with menorrhagia. Hepcidin - Hepcidin is considered a key regulator of iron metabolism; it regulates iron concentrations and tissue iron distribution via inhibition of intestinal iron absorption, iron reclamation by macrophages and iron mobilization from hepatic stores [32]. Its production is decreased in IDA and increased during inflammation and iron overloading. The overproduction of hepcidin during an acute phase response results in reduced iron absorption, mobilization, or both, contributing to the disease of anemia. Kemna et al. [33] developed the algorithm [transferrin saturation (%)sTfR (mg/l)þCRP (mg/l)¼hepcidin] to predict hepcidin levels. A strong correlation between the predicted hepcidin values and the actual measured hepcidin levels was found. Despite the selected parameters used in this algorithm, each has shortcomings; the lab indices are readily available and less expensive than serum hepcidin. Hepcidin levels have the potential to improve accuracy when differentiating between IDA and ACD.
- Ferritin — Ferritin is the cellular storage protein for iron. It is a huge (mol wt 440 kDa), 24 subunit protein consisting of light (L ferritin, 20 kd, gene on chromosome 19) and heavy chains (H ferritin, 21 kd, gene on chromosome 11) which can store up to 4500 atoms of iron within its spherical cavity [ 21 ]. H Ferritin possesses ferroxidase activity necessary for iron uptake by the ferritin molecule. An RNA binding protein (poly (rC)-binding protein 1, PCBP1) appears to be required as a cytosolic chaperone to deliver iron to ferritin [ 22 ]. Ferritin synthesis is subject to at least two levels of control, including DNA transcription via its promoter and mRNA translation via interactions with iron regulatory proteins. Ferritin is an acute phase reactant, and, along with transferrin and the transferrin receptor, is a member of the protein family that orchestrates cellular defense against oxidative stress and inflammation [ 23,24 ]. Mice lacking H ferritin die early in gestation [ 25 ]. Mice heterozygous for H ferritin have slightly elevated tissue L ferritin and 7- to 10-fold more serum L ferritin than normal mice, although they do not have tissue iron overload [ 26 ]. These observations suggest that reduced H ferritin expression in man might be responsible for cases in which high serum ferritin is present in the absence of iron overload [ 26 ]. Much of the iron stored in ferritin is accessible for metabolic needs. Ferritin within erythroid precursors may be of special importance in the donation of iron for heme synthesis, especially at the beginning of hemoglobin accumulation, at a time when the transferrin-transferrin receptor pathway is still insufficient [ 27 ]. When ferritin accumulates, it aggregates and is proteolyzed by lysosomal enzymes; it is then converted to an iron-rich, poorly characterized hemosiderin which releases its iron slowly and is detected in cells by the Prussian blue reaction. Ferritin measured clinically in plasma is usually apoferritin, a non-iron containing molecule. The plasma level generally reflects overall iron storage, with 1 ng of ferritin per mL indicating approximately 10 mg of total iron stores. Thus, A normal adult male with a plasma ferritin level of 50 to 100 ng/mL has iron stores of approximately 500 to 1000 mg [ 28 ]. A serum ferritin less than 10 to 15 ng/mL is 99 percent specific for making a diagnosis of iron deficiency. An elevated serum ferritin in the absence of infection or inflammation suggests the presence of an iron overload state. This subject is discussed in depth separately. Ferritin levels may be extremely high in patients with hemophagocytic lymphohistiocytosis or certain rheumatologic disorders. In such cases, the ferritin tends to be less glycosylated than normal. A separate ferritin (m-ferritin) is present within mitochondria and is the product of an intronless nuclear gene [ 29 ]. Its expression is increased in tissues with high numbers of mitochondria, rather than in tissues involved in iron storage [ 30 ].
- Background The transferrin receptor (TfR) is the principal means by which various organ cellular constituents acquire iron, especially erythroid precursors in the bone marrow for hemoglobin production and the placenta for iron supply to the fetus. The TfR is a 188-kDa transmembrane glycoprotein consisting of two 95-kDa polypeptide chains [1]. The TfR binds transferrin with increased avidity for diferric transferrin, whereas apotransferrin is minimally bound. Once transferrin binds to the receptor, the TfR-transferrin iron complex is internalized by formation of endocytic vesicles. Iron is released from the transferrin molecule within the vesicle under low pH conditions within the cell cytosol [2,3]; released iron is then transported out of the vesicle into the cytoplasm via dimetal-transporter II, which is incorporated into the vesicle wall. The remaining apotransferrin–TfR complex within the endocytic vesicle is transported back to the cell membrane, where apotransferrin is released back into the circulation, and TfR is incorporated into the cell membrane. Cell surface TfR concentration reflects iron requirements of the cell. When there is diminished intracellular iron available for a cell’s metabolic requirements, cell surface TfR is upregulated in an effort to acquire more iron, while cell surface TfR is downregulated when there is sufficient intracellular iron content. Ferritin content of the cell is reciprocally regulated by a unique control mechanism at the level of translation [3]. Serum contains a soluble Tfr (sTfR) molecule [4,5] that circulates bound to transferrin and is a cleaved and truncated 85-kDa form of the whole TfR molecule [1]. The circulating sTfR level reflects total body TfR concentration, the major source of sTfR being bone marrow erythroid precursors [6]. Ferrokinetic studies show a significant correlation between circulating sTfR levels and erythroid precursor mass [7,8]. Clinical Aspects and Application Erythropoiesis is highly dependent on a continuous supply of iron from the circulation. Conditions that lead to raised TfR on the surface of erythroid precursors will result in raised levels of circulating sTfR. Iron-deficient erythropoiesis is the most common cause of raised sTfR [10]. Depleted iron stores without iron-deficient erythropoiesis is not associated with raised sTfR, and is best indicated by a low serum ferritin level. As iron deficiency progresses beyond depletion of iron stores into negative iron status, with inadequate iron supply for erythropoiesis, sTfR levels begin to rise. This occurs prior to changes in any of the other standard measures of iron depletion, other than a reduction in serum iron levels [11]. Serum TfR levels continue to rise with progressive negative iron balance and progressive iron-deficient erythropoiesis, thus encompassing the entire spectrum of iron deficiency from depleted stores to iron deficiency anemia. It is important to keep in mind that sTfR levels are also elevated when erythropoiesis is significantly increased, as occurs in hemolytic anemias, disorders associated with ineffective erythropoiesis such as myelodysplastic syndromes [12], and secondary to use of erythropoiesis stimulating agents such as erythropoietin [13,14]. Certain malignancies may also raise sTfR levels—these disorders are frequently clinically evident, such as CLL [15]. Not all circulating sTfR is derived from erythroid precursors. This is evident in patients undergoing stem cell transplantation with myeloablative therapy, in whom sTfR levels fall to 50% of basal levels, indicating that other tissues also contribute to circulating sTfR [15]. The sTfR level does not usually rise to greater than three times the upper limit of normal in severe iron deficiency. The highest sTfR levels are usually seen in disorders with markedly expanded erythropoiesis secondary to chronic hemolysis plus ineffective erythropoiesis, such as the thalassemias. Measurement of sTfR is particularly useful in clinical situations in which iron stores are commonly reduced, such as pregnancy [16,17], infancy, and preschool children [18]. In these situations ferritin levels are frequently reduced, reflecting reduced, or absent iron stores, while reduced hemoglobin levels would indicate development of advanced iron deficiency. A significant proportion of these subjects have iron-deficient erythropoiesis without anemia, reflected by an elevated sTfR level. However, sTfR levels may not be increased in iron-deficient infants less than 1 year of age as recently reported [18]. These latter findings need to be confirmed. Assay of sTfR is useful in distinguishing between the anemia of chronic inflammation and iron deficiency anemia [19–21]. In contrast to serum ferritin and transferrin levels, sTfR levels are not affected by anemia of chronic inflammation or liver disease, and remain within the normal range in these disorders. When chronic inflammation may be present, measurement of C-reactive protein may be useful to confirm its presence [22]. The difference between sTfR levels in iron deficiency (increased) versus anemia of chronic inflammation (not increased) is intriguing. In both conditions, erythroid precursors exist under hypoferremic conditions, and on the basis of the rise in TfR mass in iron deficiency, one might anticipate a similar effect in anemia of chronic inflammation. It is postulated that sTfR remains within the normal range in the latter disorder due to the downregulation of intracellular TfR production by inflammatory cytokines [22,23]. This reduced TfR expression has been described at a posttranscriptional level of TfRmRNAs, secondary to interactions between iron regulatory proteins (IRPs) and iron-responsive elements in the mRNAs [23,24]. Based on current information, the recently described hepcidin protein, which is increased in anemia of chronic inflammation, does not appear to have a direct suppressive effect on TfR production. Its effect is to limit iron transport out of macrophages and gastrointestinal enterocytes, thus inducing hypoferremia. Assay of sTfR is extremely valuable when anemia of chronic inflammation and iron deficiency anemia coexist. In this situation sTfR will be raised indicating that iron deficiency is present, whereas ferritin and transferrin assays lose their ability to detect iron deficiency, since levels of these proteins are altered by the presence of inflammation [25,26]. In this situation, sTfR assay is likely to negate the need for a bone marrow examination to identify the presence of iron deficiency. Under normal circumstances, the main contributor to sTfR level is the erythroid precursor mass. Disorders of the bone marrow with decreased erythroid precursors result in reduced sTfR. After marrow ablation in bone marrow transplant patients, sTfR progressively declines corresponding to the decline in white blood cell count. The sTfR value levels out at 50% of normal during the aplastic phase, and rises with marrow recovery [15]. Low sTfR levels are seen in aplastic anemia and pure red cell aplasia, and a rise in sTfR in response to immunomodulatory therapy can be recognized weeks prior to a response in standard hematological measurements (personal observation). Serum TfR levels are also reduced in patients with iron overload disorders that are not secondary to enhanced erythropoiesis, such as genetic hemochromatosis [27]. This is in keeping with the observation of an inverse relationship between the size of the body iron stores and the mass of whole body TfR reported in animal models.
- Objective. The present study was conducted to assess the utility of serum transferrin receptor (sTfR) and sTfR ferritin indices to differentiate ACD from IDA and also to diagnose coexisting IDA and ACD. Methods. The study group comprised of 30 IDA patients, 30 cases of ACD and 30 age and sex matched controls. Complete hemogram with peripheral smear examination, markers of ACD, iron profile including serum ferritin and serum transferrin receptor levels were done in all patients and controls. Serum TfR and ferritin indices were calculated. Results. sTfR levels were significantly higher in the IDA group compared to ACD group (p<0.001). ACD group was further subdivided into two groups on the basis of sTfR levels (B1<3 μg/ml and B2 ≥ μg/ml), suggesting coexisting IDA in group B2. sTfR/log ferritin index was > 1.5 in all cases of IDA and ACD with coexisting IDA while all pure ACD cases and control subjects had sTfR/log ferritin index < 1.5. All case in IDA group had log sTfR/serum ferritin index > 2.55 and all patients with ACD with or without associated iron deficiency had log sTfR/serum ferritin ratio < 2.55. Conclusion. The sTfR levels along with the above mentioned indices can be very useful in differentiating pure IDA, ACD and ACD with coexisting iron deficiency, thus providing a noninvasive alternative to bone marrow iron.
- Use of Serum TfR/Ferritin Ratio Serum ferritin level is a useful indicator of the presence of storage iron. When iron stores are depleted, serum ferritin is below 12–15 ug/L, provided that there is no coexistent inflammation. Further deterioration of iron status will have no significant further impact on serum ferritin level, however sTfR level will begin to rise as body iron declines further and tissue iron deficiency develops. In view of these reciprocal changes in TfR and ferritin, the ratio of TfR/ferritin is a valuable measure of the extent of iron deficiency [11,28]. In a phlebotomy study in which iron status and iron deficit were calculated, the serum TfR/ferritin ratio was found to reflect body iron status and iron deficit in mg/kg body weight. The calculation may be performed as follows (using both sTfR and ferritin in ug/L10). Body iron ðmg=kgÞ ¼ ½logðTfR =ferritinÞ 2:8229=0:1207 *(This formula has only been validated using reagents employed in the current Ramco sTfR assay). Using this calculation, positive values indicate surplus storage iron, while negative values indicate a tissue iron deficit. Total iron surplus or deficit can be further refined for the individual body size and is calculated by dividing by the patient’s weight in Kg. This calculation is extremely useful in population studies, evaluating intervention strategies to improve iron status. In the evaluation of anemia, the combination of sTfR and ferritin covers the full spectrum of body iron status. A low ferritin level indicates that iron stores are depleted and raised sTfR indicates that iron-deficient erythropoiesis is present. If ferritin is elevated, C-reactive protein should be measured; if C-reactive protein is raised, serum ferritin may be inappropriately elevated due to the presence of inflammation, and loses its accuracy in reflecting iron stores [26]. However, a different ratio, TfR/log ferritin (TfR-F index) has been shown to be valuable in this situation (using the R 1 D Systems assay). If the ratio is <1, anemia of chronic inflammation is probably present, and iron deficiency is excluded, while if the ratio is >2, it is likely that iron deficiency is present along with anemia of chronic inflammation [29,30]. A ratio between 1 and 2 is indeterminate, and further evaluation may be required, including an iron stain of the bone marrow, to better assess the possibility of coexisting iron deficiency. The TfR/log ferritin ratio was shown to be superior to the TfR/ferritin ratio, sTfR alone or ferritin alone in correctly distinguishing iron deficiency anemia from anemia of chronic disease, as well as combined anemia of chronic disease plus iron deficiency (COMBI) from anemia of chronic disease alone [29]. In another study in patients having a bone marrow performed for any reason, the authors reported that sTfR had a sensitivity of 71% and specificity of 74% for correctly identifying iron-depleted marrow compared with ferritin which had a sensitivity of 25%, but specificity of 99%. A diagnostic algorithm was employed using ferritin and sTfR assays sequentially [31]. If ferritin was <25 lg/L this indicated iron deficiency, if ferritin was >300 lg/L concurrent iron deficiency was unlikely. The sTfR was performed if ferritin was between 25 and 300 lg/L, and a raised sTfR indicated COMBI. Sensitivity and specificity of this algorithm for diagnosis of iron deficiency were 67% and 93% respectively [31].
- Intermediate calculations: Blood volume (dL) = 65 (mL/kg) x body weight (kg) ÷ 100 (mL/dL) Hemoglobin deficit (g/dL) = 14.0 - patient hemoglobin concentration Hemoglobin deficit (g) = hemoglobin deficit (g/dL) x blood volume (dL) Iron deficit (mg) = hemoglobin deficit (g) x 3.3 (mg Fe/g Hgb) Volume of parenteral iron product required (mL) = Iron deficit (mg) ÷ C(mg/mL) Final calculations: Hemoglobin iron deficit (mg) = BW x (14 - Hgb) x (2.145) Volume of product required (mL) = BW x (14 - Hgb) x (2.145) ÷ C C = The concentration of elemental iron: Iron dextran: 50 mg/mL Iron sucrose: 20 mg/mL Ferric gluconate: 12.5 mg/mL
- The adverse effects of bioactive free iron resulting from parenteral iron administration have been recognized for more than 50 years. This prompted the development of formulations that shielded iron . The currently available IV preparations are all iron–carbohydrate complexes or colloids based on small spheroidal iron–carbohydrate particles. Each particle consists of a core made of an iron-oxyhydroxy gel surrounded by a shell of carbohydrate that stabilizes the gel , slows the release of iron, and maintains the resulting particles in colloidal suspension [13,15]. The currently approved IV irons all share this structure but differ from each other by the size of the core and the identity and density of the surrounding carbohydrate. The strengths of the iron complex affect pharmacokinetic characteristics of the IV irons relevant to therapeutic use. The rate of release of bioactive iron is inversely related to the strengths of the complex, the stronger the complex the slower the release of the iron . The toxicological implication of this is that stronger complexes have a lower potential to supersaturate transferrin with subsequent free iron toxicity compared to the weaker complexes. The different preparations all share the same metabolic fate. After IV injections, iron–carbohydrate complexes mix with plasma and are phagocytosed in the reticuloendothelial system. Within phagocytes, iron is released from the iron–carbohydrate complex into a low molecular weight iron pool. This iron is either incorporated by ferritin into intracellular iron stores or is released to the extracellular iron binding protein, transferrin, which delivers iron to the transferrin receptors on the surface of erythroid precursors. The resulting internalization of the iron transferrin complex supplies iron for hemoglobin synthesis. In summary, IV iron preparations are iron–carbohydrate complexes characterized by specific carbohydrates used for complexing and shielding the iron. The specific carbohydrate influences the strength of the iron complex determining the rate of release of bioactive iron. Ferumoxytol (Feraheme ®) semi-synthetic carbohydrate-coated superparamagnetic iron oxide nanoparticle safe and effective when given as a rapid intravenous infusion of up to 510 mg (infusion rate: up to 30 mg/second) in patients with CKD and ESRD Safety concerns were hypotension and/or hypersensitivity reactions (anaphylaxis and/or anaphylactoid reactions). May transiently affect the diagnostic ability of MRI
- — (Feraheme, AMAG Pharmaceuticals, Cambridge, MA)
- The nondextran IV irons, ferric gluconate and iron sucrose, have been considered to have a markedly lower serious acute event rate than the iron dextrans. In 1999, Faich and Strobos [32] compared the spontaneous reports to the US and European Drug agencies of serious reactions to iron dextrans and non-iron dextrans. They noted a significantly higher rate of reactions and 31 deaths attributed to iron dextrans, while no deaths were attributed to the nondextran irons. In 2002, Michael et al. [33] found a very low reaction rate with ferric gluconate in 2,534 hemodialysis patients in a double-blind, placebo controlled, study in ferric gluconate naı¨ve patients. They also noted that patients having reactions to ferric gluconate did not exhibit an increase in tryptase, a marker of mast cell degranulation [34]. An increase in tryptase would be expected if reactions were true anaphylaxis. They also compared those results to the published reaction rate to iron dextrans, and concluded that ferric gluconate was much safer than iron dextran. None of these papers were able to differentiate the reaction rate of HMW versus LMW iron dextran preparations. A similarly low reaction rate has been reported in open label studies of iron sucrose. In 1996, Silverberg [35] showed that approximately 20% of dialysis patients could have anemia effectively treated with iron sucrose alone. He recommended administering sufficient iron sucrose to increase serum ferritin to 200–400 lg/L and/or iron saturation up to 25–35% before considering EPO. Aronoff et al. [36] reported repeated doses of iron sucrose in 665 hemodialysis patients receiving EPO was well tolerated, including 80 patients (12%) considered intolerant to an iron dextran. Black box warnings do not appear in the package inserts of either ferric gluconate or iron sucrose. As a result, these two products have rapidly replaced iron dextran, and TDI because of little interest in nephrology except in patients on peritoneal dialysis. These nondextran irons bind iron less avidly than dextran, and this is believed to account for dose and infusion rate dependent acute vasoactive reactions o iron sucrose and ferric gluconate. Typical reactions include low blood pressure, abdominal discomfort, and back pain, and resolve with cessation of the infusion and time. The current highest recommended dose for ferric gluconate is 125 mg IV push over 5–10 min (Ferrlecit package insert) and for iron sucrose, 200 mg IV push or 300 mg over 2 hr. Doses greater than 300 mg are not recommended [37]. In a review of the US Food and Drug Administration (FDA) database of spontaneous AE reporting, Chertow et al. [38] found no significant differences in life threatening or fatal serious AEs when ferric gluconate and iron sucrose were compared to LMW ID, although these reports are highly insensitive in as much as they reflect only reported events and under-estimate actual reaction rates many-fold. A follow-up analysis [39] examined reactions to iron sucrose, and concluded that the frequency of IV iron related AEs with all products has decreased, and overall the rates were extremely low. The reported incidence of serious AEs among LMW ID, ferric gluconate, and iron sucrose are similar with an estimated incidence of <1:200,000. Similarly, Fletes et al. [40] found an 8-fold higher AE rate associated with the use of HMW ID (Dexferrum) that could not be explained by differences in patient or facility characteristics. McCarthy et al. [41] reported a nearly 3-fold increase in AEs with HMW ID than with LMW ID. This suggests that the incidence of acute reactions for iron dextran believed to be correct (0.3%) is related to the use of HMW ID and the rate with LMW ID is far lower. Subsequently, three studies [42–44] comparing the efficacy of safety of LMW ID and iron sucrose found no differences in efficacy or toxicity between the two iron preparations. These recent studies conflict with earlier claims of lower reactions rates to nondextran irons based on comparison to historical controls or exposure of patients with prior allergies to these new agents [33,45]. In the last decade three events occurred that would markedly affect the practice of IV iron administration. First, the work of Abels, Glaspy, Henry, Gabrilove, Littlewood, and others [46–50], showed that EPO was of great benefit in correcting anemia in patients with cancer or receiving cancer chemotherapy. Second, ferric gluconate (Ferrlecit, Schein Pharmaceuticals) and iron sucrose (Venofer, American Regent Pharmaceuticals), two products that had been used extensively in Europe and Asia for years, were approved as parenteral iron supplements in the United States. Third, studies [49,52–54] proved that IV iron administered with EPO for the anemia of cancer and cancer chemotherapy more than doubled the response rate compared to EPO alone. All of these trials will be discussed later in the text.
- Unfortunately, this event continues to be misconstrued as an anaphylactoid reaction prompting intervention with drugs such as diphenhydramine and epinephrine, each of which is able to cause severe cardiovascular side effects. Although the National Comprehensive Cancer Network guidelines suggest pretreatment with diphenhydramine and acetaminophen to help reduce the risk of adverse reactions [25], the use of antihistamines can cause vasoactive reactions that may be misinterpreted and are often attributed to the injected iron. Premedication with cimetidine, dexamethasone, and diphenhydramine associated with more adverse effect
- Abstract BACKGROUND: Correction of iron deficiency is critical in chronic hemodialysis patients, and intravenous administration is superior to the oral route in this goal. Recently, concern was raised that intravenous iron administration might promote infection in dialysis patients. METHODS: We reviewed the data from a recent prospective study of 985 patients in which no link between iron therapy and bacteremia had been found. We tested the potential role of the administration route of the iron (intravenous vs. oral), the weekly amount of iron administered and the administration rate on the risk for bacteremia in these patients. RESULTS: were 4-fold: in multivariate analysis, neither intravenous iron administration in the whole population nor the weekly amount of iron in the subgroup of i.v. iron-treated patients were significant risk factors for bacteremia; iron was not given more frequently intravenously in bacteremic than in non-bacteremic patients; among patients treated with intravenous iron, the frequency and the amount of iron administered were significantly higher in those who developed bacteremia than in those who did not; and in patients receiving i.v. iron, there was an increased risk of bacteremia associated with concurrent administration of erythropoietin, which was not observed in patients receiving iron orally. CONCLUSION: This study failed to demonstrate a significant association between intravenous iron administration and the risk of bacteremia in dialysis patients. However, there might be a slightly increased risk of bacteremia in patients given high-frequency, high-dose intravenous iron.
- Safety concerns relating to the administration of i.v. iron include the rare but potentially fatal cases of anaphylaxis reported with iron dextran43, mediated by preformed dextran antibodies44. Anaphylaxis has since been shown to be much less frequent with low-molecular-weight forms of iron dextran45 but nevertheless the European Best Practice Guidelines do not generally recommend use of iron dextran due to the risk of life threatening acute reactions 15. With other i.v. preparations, notably iron sucrose and iron gluconate, true anaphylaxis does not occur, although occasional non-life threatening ‘labile iron’ reactions can occur44. These are very infrequent: in an analysis of all adverse events reported to the Food and Drug Administration (FDA) during 1997–2002, the rate of urticaria was 0.32 and 0.80 per million 100 mg iron dose equivalents with iron sucrose and sodium ferric gluconate respectively46. No ‘anaphylactoid reactions’ at all have been reported with iron sucrose on the FDA database, and the rate of such events with sodium ferric gluconate is only 0.46 per million 100 mg iron dose equivalents. Based on evidence to date, the new rapid high-dose i.v. iron preparations appear to offer an acceptable safety profile. Newer preparations (ferric carboxymaltose and ferumoxytol) have recently been developed and permit faster, high-dose administration without the need for a test dose44. In a randomised study of ferric carboxymaltose (1000 mg iron in a single dose over 15 minutes, with up to two further 500 mg iron doses) undertaken in 250 non-dialysis patients, the rate of drug-related adverse events was lower with ferric carboxymaltose than with oral iron (2.7 vs. 26.2%) and no serious adverse drug events or hypotension occurred47. Consistent with this, a pooled analysis of 2800 patients given ferric carboxymaltose for iron-deficiency anaemia secondary to various conditions demonstrated a lower rate of drug-related adverse events with ferric carboxymaltose (15.3%) compared to oral iron (26.1%), with no serious/life-threatening hypersensitivity events or symptomatic hypotensive episodes following administration of the i.v. preparation48. Similarly, ferumoxytol has shown a lower incidence of adverse events than oral iron in a large randomised trial of CKD patients (35.5 vs. 52.0%), with only dizziness occurring more frequently in the ferumoxytol arm23. Drug-related adverse events occurred in 10.6% of patients in the ferumoxytol arm versus 24.0% of the patients randomised to oral iron. Neither hypersensitivity nor hypotension was observed in the ferumoxytol-treated patients. As novel agents, the safety evidence base for both ferric carboxymaltose and ferumoxytol is inevitably less extensive and of shorter duration than for long-established formulations such as iron sucrose, and ongoing monitoring is important. Reflecting this, the FDA has requested further safety data on ferric carboxymaltose from additional clinical studies, which are currently underway. As a result, the preparation is not yet licensed in the US. Of the main safety concerns related to conventional i.v. iron formulations, the acute reactions seen with iron dextran are unlikely to prove an issue for either ferric carboxymaltose or ferumoxytol, and the drug regulatory authorities have not stipulated test dosing for these agents (European Medicines Agency [EMEA] in the case of ferric carboxymaltose and the FDA in the case of ferumoxytol). It is also possible that increased oxidative stress, a further concern with conventional preparations, would be less frequent with the novel formulations. Animal data that ferric carboxymaltose may have a favourable safety profile in terms of oxidative stress compared to iron dextran and ferric gluconate await confirmation
- and resultant iron restricted erythropoiesis. Proinflammatory cytokines are important contributors to the hypoferremia and anemia seen in chronic diseases. In chronic inflammatory states iron acquisition by macrophages takes place mainly through erythrophagocytosis and the transmembrane transport of ferrous iron by the protein divalent metal transporter 1 (DMT 1) [55]. The proinflammatory cytokines interferon gamma, lipopolysaccharide, and tumor necrosis factor alpha upregulate DMT 1 expression resulting in an increased uptake of iron into activated macrophages and also induces the retention of iron in macrophages by downregulating the expression of ferroportin. Consequently iron release from macrophages is blocked [56]. Ferroportin, a transmembrane exporter of iron, is believed to be responsible for the transfer of absorbed ferrous iron from duodenal enterocytes into the circulation [57]. Hepcidin, an iron regulatory acute phase protein, has been shown to have an important role in the pathophysiology of ACD. Expression of hepcidin is induced by lipopolysaccharide and interleukin 6 and is inhibited by tumor necrosis factor alpha [58]. Hepcidin is believed to be involved in the diversion of iron traffic by decreasing duodenal iron absorption and blocking iron release from macrophages. A recently identified gene, hemojuvulin, may act in concert with hepcidin to induce these changes [59]. The net effect of these alterations in iron homeostasis is a limitation of the availability of iron for erythroid progenitor cells and impairment of their proliferation by negatively impacting on heme biosynthesis. In summary, in anemias of chronic diseases, the increase in inflammatory cytokines causes an increase in hepcidin with a subsequent decrease in iron absorption. When inflammatory cytokines are not present, hepcidin levels are much lower and GI absorption of oral iron can more freely occur. This is supported by data in patients with hereditary hemochromatosis, where a mutated HFE gene decreases hepcidin levels and allows unimpeded iron absorption to occur [60].
- (30 colon cancer resections, 33 abdominal hysterectomies, 21 lower limb arthroplasties) One third to one half of preop patients have anemia. Postop – 90% of patient have anemia
- Long term studies assessing the risks and benefits of different IV iron preparations are needed. As of this review there exist no clear practice guidelines for IV iron as an adjunct to ESA therapy outside nephrology. Randomized trial data have shown the efficacy of IV iron in epoetin-treated patients, even among patients with elevated ferritin (500–1,200 ng/mL) with TSAT 25% [70,71]. Among dialysis patients, who frequently have elevated ferritin from inflammation, reliable predictors of a hematological response to IV iron have not been found [71]. The nephrology literature is rife with publications showing IV iron reduces ESA dose even in patients with iron parameters consistent with an iron repletion state [28]. These data are corroborated by publications in the oncology literature [51,52,54,61] in which hemoglobin response occurs in patients with transferrin saturations as high as 50% [61] and in patients with positive marrow hemosiderins [52].
- The retrieval of iron is essential to bacterial survival and represents a factor for which both host and pathogen compete. Conditions including hemochromatosis, in which the level of iron in serum is increased, compromise host defenses and increase predisposition to various bacterial and nonbacterial infectious diseases. This excess iron burden does not only help the propagation of pathogens, but also plays a sentinel role in modifying the host immune mechanism, specifically by impairment of cell-mediated immune responses. Hepcidin has recently emerged as an important bridge between innate immunity and iron metabolism and is thought to be responsible for augmentation of the host response to pathogens. Functional impairment of hepcidin due to high iron concentrations has therefore been associated with the increased susceptibility for infections in these patients. It must be noted that most of the cases reported in this review are based on case reports, but nonetheless may be helpful to physicians in expanding differential diagnoses when faced with similar situations. Often the diagnosis of hemochromatosis in these patients is an incidental finding and physicians should therefore consider evaluation for the diagnosis of hemochromatosis when faced with infections caused by certain organisms as described. Alternatively clinicians should consider various pathogens in patients with hemochromatosis who present with a febrile illness. Modulation of iron metabolism, including use of recombinant hepcidin in patients with hemochromatosis and infectious diseases, is an area that warrants further research.