Bogdan Dumitriu, Jeffrey Miller and Griffin P. Rodgers
Iron deficiency is the most common cause of anemia throughout the world, with over 1 billion people being affected.1 In the United States 10% of women of childbearing age and young children are iron deficient.2 Functional iron deficiency is more common in elderly patients, who have a high frequency of anemia resulting from inadequate utilization of iron stores.3 Clinical presentation includes fatigue, weakness, headaches, pallor, stomatitis, and glossitis. Presenting symptoms may also include appetite for nonnutritional or unusual food items (pica), restless leg syndrome,4 or beeturia.5 While described in cases of severe iron deficiency, Plummer-Wilson syndrome (dysphagia, esophageal webs, atrophic glossitis with iron deficient anemia), koilonychias (spoon nails), chlorosis (greenish color of skin), or blue sclerae are very rarely found at presentation in modern industrialized countries.
ABSOLUTE VERSUS FUNCTIONAL IRON DEFICIENCY
Iron deficiency anemia is caused by:
Decrease in total body iron (“absolute” iron deficiency)
Inadequate utilization of iron stores (“functional” iron deficiency)
IRON METABOLISM
Approximately half of the 3 to 4 g of total body iron is contained in the hemoglobin of circulating red cells (Fig. 1.1). Nonerythroid iron is contained in reticuloendothelial system (RES), myoglobin, and the liver. Intracellular iron is stored in ferritin, and the circulating level of ferritin normally correlates closely with the intracellular iron stores.6
The average daily requirement of iron to support erythropoiesis is 20 mg. Most of the daily iron requirement is supplied by recovery of erythroid iron through phagocytosis of senescent erythrocytes by RES. Daily, 1 to 2 mg of iron is obtained from dietary intake to compensate for losses in sweat, urine, and feces.7 For women during the childbearing years, there are additional losses due to menstruation (average of 0.3–0.5 mg iron/day).8 To balance these losses:
Adult males must absorb about 1 mg of iron each day from their diet, and menstruating females require about twice this much.
During pregnancy and periods of rapid growth, iron balance must be positive in order to support increased production of hemoglobin and myoglobin.
Negative iron balance results from increased loss of iron (nearly always due to bleeding), inadequate dietary intake, and increased utilization of iron (Table 1.1).
FIGURE 1.1 The iron cycle. RES, reticuloendothelial system.
Dietary iron is present in ferric (Fe+3) salts in meat and vegetables and in heme in meat.7 Heme iron is the most bioavailable because it is soluble at the alkaline pH of the duodenum, where it is absorbed as an intact iron–porphyrin complex. In contrast, ferric iron is not soluble at alkaline pH and is not absorbable by the duodenal mucosa. To be absorbed, it must be solubilized in the acidic stomach where it is loosely complexed with small molecules such as amino acids. Ferric reductase in the duodenal mucosa reduces the iron to its divalent state, which can be transported into enterocytes.9 The enhancing effect of ascorbate on iron absorption results from increased solubilization of ferric iron, as well as increased ferric reductase activity.10 In contrast, absorption of ferric iron is impaired by achlorhydria and by foods containing chelators of iron, such as tannins and phytates, which are prevalent in tea and cereals. Although medicinal iron is in ferrous state, thus presumably unaffected by these factors, it is still recommended to have a 2-hour delay in taking anything that might impair absorption.
Ferrous iron is released from duodenal enterocytes via the exporter ferroportin, which is regulated by the hormone hepcidin, and becomes oxidized to ferric iron before binding to transferrin.9 Hepcidin binding to ferroportin induces internalization and degradation of ferroportin, thus decreasing cellular iron export.11 The same export mechanism exists in macrophages and hepatocytes.12
Once released in circulation, iron binds transferrin.9 Each transferrin molecule can bind one or two iron atoms. Diferric transferrin is taken up by developing red cells more easily than monoferric transferrin and delivers twice as much iron per molecule.13 Therefore, the concentration of diferric transferrin is critical to the support of erythropoiesis. Steady state erythropoiesis requires a serum concentration of diferric transferrin that is achieved when the transferrin saturation is at least ~16%.14
ABSOLUTE IRON DEFICIENCY
A negative iron balance depletes body iron stores before iron deficient erythropoiesis occurs.15 Multiple laboratory parameters associated with iron depletion state precede anemia (Table 1.2).
Table 1.1 Causes of Absolute Iron Deficiency
Increased Loss of Iron
Bleeding
Menorrhagia
Gastrointestinal
Surgery
Trauma
Childbirth
Excessive phlebotomy
Blood donations
Factitious
Hemodialysis
Hematuria
Chronic hemoglobinuria
Mechanical heart valve hemolysis
Paroxysmal nocturnal hemoglobinuria
Decreased Intake of Iron
Dietary deficiency
Limited meat
Malabsorption
Achlorhydria
Gastric atrophy
Partial gastrectomy
Gastric bypass
Proton pump inhibitors
Helicobacter pylori gastritis
Inflammatory bowel disease
Celiac disease
Increased Utilization of Iron
Pregnancy or lactation
Rapid growth
Stainable marrow iron (RES hemosiderin) and serum ferritin are the primary markers of a negative iron balance. Serum ferritin accurately reflects body iron stores. Thus a bone marrow biopsy is rarely needed. Serum ferritin below ~30 ng/dL is indicative of absolute iron deficiency, while in the presence of inflammation or liver disease the cutoff is higher (~100 ng/mL). 16
Reticulocyte hemoglobin is reported as part of the automated profile of reticulocytes. Due to the long half-life of mature erythrocytes in the circulation, reduced hemoglobin content in reticulocytes may be useful in cases of acute iron deficiency or for monitoring response to iron repletion therapy. In the absence of thalassemia, reticulocyte hemoglobin values below 26 pg per reticulocyte indicate early iron deficiency. 17
As storage iron becomes depleted and the iron supply to red cells becomes limiting, an increase in circulating transferrin receptors was reported.18 Elevated serum soluble transferrin receptor concentrationis not specific for iron deficiency and can be associated with erythroid hyperplasia. While a recent prospective multicenter trial suggested an added benefit of identifying absolute iron deficiency when anemia of chronic disease was also present,19 it is not generally recommended for use in clinical practice.18
When the storage iron becomes depleted, serum iron and transferrin saturation begin to drop while the transferrin concentration usually rises.
When transferrin saturation reaches ~16%, the supply of iron to developing red cells becomes rate limiting, and the red cell count begins to decrease.
The new iron deficient red cells are smaller than the older ones, and therefore the red cell distribution width (RDW) begins to increase.
When microcytes become more numerous, the mean cell volume (MCV) falls below the normal range, typically when the hemoglobin reaches ~10 g/dL.
FUNCTIONAL IRON DEFICIENCY
Hypoferremia despite seemingly adequate iron stores due to increased erythropoietic activity can be driven by endogenous erythropoietin stimulation as for patients recovering from absolute iron deficiency if the rate of supply of iron from their stores limits the rate of red cell production.20 During pregnancy, iron requirements increase to 5 to 7 mg/day, so iron supplementation is needed to prevent the depletion of iron stores.21 Erythropoietin-stimulating agents (ESA) administration in patients with chronic kidney disease (CKD) also causes increased erythroid iron demand, although iron sequestration also plays a role. These patients may have adequate iron stores, but their response to ESA is blunted until they are given iron supplementation.22 Thalassemia major leads to increased iron absorption and ultimately to iron overload due to high erythropoietic activity as well as pathological mechanisms caused by ineffective erythropoiesis.23
Anemia of chronic inflammatory states or anemia of chronic disease (ACD) accounts for most of iron sequestration syndromes but rare causes like hepcidin-producing adenomas, copper deficiency, and iron refractory iron deficiency anemia (IRIDA) have been described.24 ACD develops in patients with chronic infectious, inflammatory, or neoplastic diseases. The anemia associated with functional iron deficiency is usually mild and asymptomatic.25Although usually normocytic, the MCV is often on the low end of normal and may be in the microcytic range. The serum iron concentration and transferrin saturation often suggest absolute iron deficiency, but the transferrin concentration is not elevated and may be low.25 Furthermore, there is evidence of storage iron in the form of an elevated serum ferritin, as well as stainable iron in the bone marrow.
Patients with chronic illnesses can also have absolute iron deficiency, which can be particularly difficult to diagnose because of the effects of inflammation on the laboratory parameters of iron status. Chronic inflammation, for example, can suppress transferrin and elevate serum ferritin even in the true absence of storage iron.26
Hepcidin biology is being aggressively developed for iron-related diseases. Diagnostic27 and therapeutic28,29 applications have been proposed (Table 1.3). More robust assays are needed before hepcidin levels become generally available in the clinic.30 However, research studies have already shown that serum hepcidin levels are very low or at undetectable levels in patients with absolute iron deficient anemia.31 In contrast, iron administration upregulates hepcidin in healthy volunteers.32 Importantly, hepcidin is increased by the inflammatory cytokines such as interleukin-6.33 Therefore, patients with increased inflammatory states possess a wide range of serum hepcidin levels (100–4,000 ng/mL) when compared with healthy volunteers (5–350 ng/mL).31
TREATMENT OF IRON DEFICIENCY ANEMIA
Dietary Iron
Dietary review and counseling is needed for all patients evaluated for iron deficiency. Iron malabsorption or inhibition of absorption by other substances needs to be evaluated. Non-vegan patients should be encouraged to increase red meat or liver in their diet, as well as vitamin C, known to increase iron absorption. Because the heme of meat is so readily absorbed and without gastrointestinal side effects, it is an excellent source of iron. The presence of heme in the diet also increases the absorption of inorganic iron. Patients presenting with anemia usually require more than just diet supplementation.34
Oral Iron Therapy
Several oral iron formulations are available, all containing iron sulfate, gluconate, or fumarate (Table 1.4). Most of them are tablets, non–enteric coated, enteric-coated, or slow release, but they can also be elixirs, usually containing less elemental iron.
Slow release or enteric-coated formulations of iron are touted to cause fewer gastrointestinal side effects, but they also often contain less iron per dose and are considerably more expensive than the nonenteric salts (see Table 1.4). Furthermore, they may release their iron below the duodenum, too distal for significant absorption.
A daily supplement of ~200 mg of elemental iron taken in a fasting state provides the marrow with enough iron to raise the blood hemoglobin concentration up to 0.25 g/dL/day in severely anemic patients.35Oral iron, however, causes nausea or constipation in some patients. Because these symptoms correlate with the amount of iron ingested, the dose should be lowered until tolerable or the medication should be stopped altogether until the symptoms resolve and then restarted at a lower dose. Using an elixir of iron allows doses as low as 10 to 20 mg of elemental iron, and multivitamins often contain even smaller amounts. Low doses of iron can be therapeutic; the response is just slower.36 Patients should be prescribed stool softeners as needed. Often they can avoid nausea by taking their iron with food. This practice reduces iron absorption, but it usually does not make patients refractory to iron. Alternatively, bedtime dosing may be used to increase the tolerability to oral formulations.
A variety of medications can reduce oral iron absorption (Table 1.5) and should not be taken within several hours of iron tablets. Conversely, oral iron supplements can hinder the absorption of other medications (Table 1.6).
Oral iron absorption testing may be considered for patients suspected of malabsorption.37 An 8 to 12 hour fasting serum iron is compared with the iron serum level 1 hour after ingestion of 65 mg of elemental iron (325 mg tablet of ferrous sulfate). An increase in serum iron of over 100 µg/dL from baseline demonstrates adequate absorption. In case of malabsorption, gastrointestinal consultation should be sought to identify and treat reversible etiologies. Parenteral iron treatment may be considered in cases of iron malabsorption (post-gastric bypass surgery, celiac disease, autoimmune gastritis, and Helicobacter pyloriinfection).38
Table 1.6 Medications Malabsorbed When Co-administrated with Iron
Quinolone antibiotics
Thyroxine
Biphosphonates
Penicillamine
Cefdinir
Mycophenolate mofetil
Levodopa, carbidopa, methyldopa
Zinc or copper salts
Data from Lexicomp.com.
Iron supplements should be taken until the anemia resolves, which may only require a few weeks. Additional supplements are required to replenish iron stores. Several algorithms can be used to decide the length of the therapy (Table 1.7). The rate of iron absorption becomes slower once the patient is no longer anemic,37 so serum ferritin levels may be followed to determine when iron stores are replenished. Once the anemia is reversed, a serum ferritin of 40 to 50 µg/L should be reached before the supplements are discontinued.39
Intravenous Iron Therapy
CKD and dialysis patients receiving ESA require intravenous (IV) iron therapy.40 When compared with oral iron treatment, administration of 100 mg of IV elemental iron twice weekly required 46% less erythropoietin to maintain same hematocrit goal.41 Other inflammatory states associated with anemia benefit from the combination of ESA and IV iron, including inflammatory bowel disease (IBD), rheumatoid arthritis, and malignancy.24 Other indications include patients that cannot tolerate an adequate dose of oral iron, such as during pregnancy, or when they have severe and recurrent gastrointestinal or uterine hemorrhage.
Four formulations of parenteral iron are currently marketed in the United States: iron dextran (DexFerrum™, INFeD™), sodium ferric gluconate in sucrose (Ferrlecit™), iron sucrose (Venofer™), and Ferumoxytol (Feraheme™) (Table 1.8). Until 1999 when FDA approved Ferrlecit™ for treatment of anemia in renal failure patients, iron dextran formulations were the only available option. Iron dextran is now the only formulation that requires a test dose and premedication due to reported anaphylactic reactions. Because fewer adverse events were reported with the non-dextran formulations,42 iron dextran is being replaced in clinical practice. For all preparations, the infusion can be repeated weekly depending on the iron deficit magnitude. Increased amount of elemental iron per dose with newer formulations allows for more rapid correction of the iron deficit, with fewer hospital visits, as well as increased compliance.43 The clinical effects of the oxidative stress and other inflammatory changes reported with parenteral iron treatment are not fully understood.40
Red Blood Cell Transfusion
Red blood cell transfusion is reserved for acute presentation in hemodynamically unstable patients. The iron content of packed red blood cells (PRBCs) is around 1.0 mg of heme iron per 1.0 mL of packed erythrocytes. After one unit of PRBCs is transfused, the expected increase in hemoglobin and hematocrit is 1 g/dL and 3%, respectively.44 It may take 2 to 3 weeks for the effects of transfused PRBCs to be realized in the iron parameters.45
RESPONSE TO IRON THERAPY
When iron is given orally in full doses or parenterally to otherwise healthy individuals,
within 3 or 4 days, peripheral blood reticulocytes increase
within the first week, the hemoglobin begins to rise
A failure to observe a rise in hemoglobin after 1 to 2 weeks can be due to an incorrect diagnosis of iron deficiency, continued bleeding (in which case reticulocytes will increase despite no improvement in the anemia), noncompliance with the therapy, malabsorption for oral iron therapy, or a combination of these factors.
TREATMENT OF FUNCTIONAL IRON DEFICIENCY
Increased iron requirements during stress erythropoiesis can be addressed with either oral or parenteral iron administration. In pregnancy, parenteral iron may be required due to intolerance to oral formulations. ESA treatment in patients with CKD or end stage renal disease (ESRD) requires adequate iron stores. Iron supplementation for dialysis patients is usually parenteral.40
In iron sequestration syndromes, the only truly satisfactory solution is adequate treatment of their underlying cause. Although the anemia is typically mild, treatment with iron supplements should be attempted for those patients with more severe anemia who are being considered for transfusion therapy. Parenteral iron supplementation may be helpful due to decreased oral absorption.25 Although giving both erythropoietin and iron can eliminate the need for red cell transfusions, the effect of this combination on a patient’s distribution of iron is the same as that of transfusions: iron accumulates in inaccessible stores. Long-term safety studies are needed to determine the iron dosing schedules and limits in this clinical setting.
Treatment of Anemia in Patients with Advanced Malignancy
Advanced malignancies, as well as their treatment with chemotherapy, puts patients at a higher risk of anemia. In this setting, support with parenteral iron and ESA is the standard approach. Oral iron has been shown to be inferior to parenteral iron in patients receiving ESA for chemotherapy-induced anemia.46 Multiple studies in recent years have shown a decreased survival in patients with different malignancies when receiving ESA.47 Increased risks of thromboembolic disease, pro-angiogenic effects, as well as elevated blood pressure are proposed mechanisms.47 The Food and Drug Administration (FDA) recently issued a black box warning for cancer patients receiving ESA. A mandatory risk assessment online tool was also provided at www.esa-apprise.com. Further recommendations for ESA usage are addressed in this handbook’s appendix.
Treatment of Anemia Associated with Chronic Inflammatory Diseases
The anemia of rheumatoid arthritis has been reported to respond to parenteral iron alone, as well as to ESA alone, with elevations of hemoglobin from ~11.5 to ~12.5 g/dL in both instances.48,49 An additive effect was reported when adding parenteral iron to ESA in one series.50 In IBD, (1) absolute iron deficiency is common, (2) the anemia typically responds to iron alone, (3) parenteral iron is usually required because of gastrointestinal intolerance, and (4) erythropoietin can magnify the erythroid response.51 In contrast, anemic patients with chronic infections, including HIV, should receive iron only if they have absolute iron deficiency, because of concern that an increased iron supply may promote the growth of certain microorganisms that are siderophoric like Yersinia enterocolitica or Klebsiella pneumoniae.52,53
SUMMARY
Iron deficiency anemia remains one of the most prevalent health problems in United States and worldwide despite improved understanding of its pathophysiology and the availability of more oral and parenteral supplementation options. In addition to assessment of the hematological status and iron parameters, effort should always be made to determine the cause of absolute or functional iron deficiency. In cases of hemorrhage or nutritional iron deficiency, the diagnosis and case management are usually accomplished in the primary care setting.
Specialized care is indicated when no cause is identified or the patient does not respond to oral therapy. In some cases, parenteral iron formulations may be required. Based on improved safety profiles, administration of parenteral iron may be provided in the outpatient setting. Iron replacement regimens should be designed to correct the anemia and to additionally replenish iron stores. Rapid advances in iron and hepcidin biology are predicted to improve future diagnostic and therapeutic approaches to this disease.
References