Minapharm Pharmaceuticals



Treatment of the adult with iron deficiency anemia

Authors

Stanley L Schrier, MD

Michael Auerbach, MD, FACP

Section Editor

William C Mentzer, MD

Deputy Editor

Stephen A Landaw, MD, PhD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Apr 2013. | This topic last updated: Mar 25, 2013.

INTRODUCTION — The management of adults with anemia due to iron deficiency, including the relevant diagnostic and therapeutic issues as well as the choice of iron preparation, will be discussed here.

The causes and diagnosis of iron deficiency are discussed separately, as is the treatment of iron deficiency in infants and young children and adolescents. (See "Causes and diagnosis of iron deficiency anemia in the adult" and "Iron deficiency in infants and young children: Treatment" and "Iron requirements and iron deficiency in adolescents".)

The uses of iron preparations for the treatment of functional iron deficiency in patients with chronic kidney disease as well as malignancy being treated with erythropoietin are specialized subjects and are presented separately. (See "Iron balance in non-dialysis, peritoneal dialysis, and home hemodialysis patients" and "Use of iron preparations in hemodialysis patients" and "Diagnosis of iron deficiency in chronic kidney disease" and "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Iron monitoring and supplementation'.)

MANAGEMENT OVERVIEW — The usual presenting symptoms in adults, as seen in current practice, are primarily due to anemia, and include weakness, headache, irritability, and varying degrees of fatigue and exercise intolerance. However, many patients are asymptomatic and may recognize that they had fatigue, weakness, exercise intolerance, pagophagia (ice craving, a form of pica), or restless legs syndrome only after successful treatment with iron. (See "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Clinical manifestations'.)

Public health aspects — More than a quarter of the world’s population is anemic, and about one-half of this burden is a result of iron deficiency anemia, being most prevalent among preschool children and women. The prevention and treatment of iron deficiency is obviously a major public health goal, especially in low- and middle-income countries, although the various aspects of this issue are complex and beyond the scope of this review [1]. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis", section on 'Prevention of iron deficiency' and "Iron requirements and iron deficiency in adolescents", section on 'Iron supplements' and "Nutrition in pregnancy", section on 'Iron' and "Overview of dietary trace minerals", section on 'Iron'.)

Diagnostic issues — Successful overall management of the patient with iron deficiency anemia requires an attempt to identify and treat the underlying cause(s) of the iron deficiency (eg, blood loss from a tumor, varicosity, or other bleeding lesion; iron malabsorption). (See "Causes and diagnosis of iron deficiency anemia in the adult".)

Treatment issues — The choice of iron preparation depends upon the acuity of illness, as well as the ability of the patient to tolerate oral iron preparations. (See 'General principles' below.)

▪ Oral iron therapy — Because oral iron is inexpensive and effective when taken as prescribed, it is considered front line therapy. There are numerous conditions, however, for which oral iron is either poorly tolerated or ineffective. As examples:

• Gastrointestinal side effects are extremely common and may result in poor adherence to therapy. It is estimated that more than 70 percent of some populations to whom oral iron is prescribed do not take it [2].

• Various malabsorptive states (eg, celiac disease, Whipple’s disease, bacterial overgrowth syndromes) may be associated with an inability to absorb iron optimally. (See 'Failure to respond to oral iron therapy' below and "Regulation of iron balance", section on 'Intestinal iron absorption'.)

• Treatment with oral iron may take as long as six to eight weeks in order to fully ameliorate the anemia, and as long as six months in order to replete iron stores.

• In patients with inflammatory bowel disease, the use of oral iron has been associated with worsening of the underlying disease, and may be poorly tolerated and ineffective [3]. (See "Nutrient deficiencies in inflammatory bowel disease", section on 'Iron'.)

• In conditions such as heavy uterine bleeding, hereditary hemorrhagic telangiectasia, gastric bypass, or other causes of heavy blood loss, absorption of oral iron, even in maximal doses, may be unable to keep up with blood loss.

• Dialysis patients, especially those being treated with erythropoiesis-stimulating agents (ESAs), are unable to fully utilize iron administered orally [4,5]. (See "Iron balance in non-dialysis, peritoneal dialysis, and home hemodialysis patients", section on 'Indications for oral versus intravenous iron therapy'.)

• Non-dialysis chronic kidney disease patients have a number of reasons for their inability to absorb oral iron (eg, impaired iron transport, concomitant use of calcium-containing salts, H2 blockers, phosphate binders, generalized malabsorption) [6].

• Oral iron, unlike the intravenous preparations, does not synergize well with ESAs (eg, erythropoietin, darbepoetin) in anemic cancer patients both on and off chemotherapy [7,8]. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Iron monitoring and supplementation'.)

• Inflammation-mediated induction of hepcidin, which regulates iron homeostasis, may result in suboptimal gastrointestinal absorption of orally administered iron in iron deficient subjects [9]. Non-response to oral iron therapy did not rule out iron deficiency in such subjects, since two-thirds of the non-responders in this study responded to treatment with intravenous iron. (See "Anemia of chronic disease (anemia of chronic inflammation)", section on 'Supplemental iron'.)

• Over a quarter of the world's population remains anemic; about half of this burden is due to iron deficiency anemia (IDA). Strategies to control IDA include daily and intermittent iron supplementation, home fortification with micronutrient powders, fortification of staple foods and condiments, and activities to improve food security and dietary diversity [1]. The safety of routine iron supplementation in settings where infectious diseases such as malaria are endemic remains uncertain.

▪ Parenteral iron — Clinicians’ historical reluctance to use parenteral iron preparations more widely can be traced, at least in part, to severe side effects (eg, anaphylaxis, shock, death) associated with earlier parenteral iron preparations, such as high molecular weight iron dextran. However there are numerous settings in which the use of intravenous iron preparations may be preferable. As examples:

• With the advent of parenteral iron formulations with improved toxicity profiles, the early switch to intravenous iron should be considered in those intolerant to the use of oral iron preparations. (See 'Parenteral iron therapy' below.)

• It has been estimated that the maximum amount of elemental iron that can be absorbed with an oral iron preparation is 25 mg/day [10], whereas, depending upon the preparation used, up to 1000 mg of elemental iron can be administered following a single infusion of intravenous iron. (See 'Available preparations' below.)

• Intravenous iron is effective for those unresponsive to or intolerant of oral iron. Published evidence supports the consideration of intravenous iron as an early option for those with inflammatory bowel disease (IBD) [3]. As a result, intravenous iron is considered frontline therapy in Europe for iron deficiency anemia associated with IBD with or without oral iron intolerance or ineffectiveness [3]. For patients with chemotherapy induced anemia, NCCN Guidelines state that intravenous iron is the preferred route when iron supplementation is indicated, and K/DOQI guidelines indicate its use for iron replacement in dialysis patients. These issues are discussed in greater detail elsewhere in UpToDate.

• Intravenous iron is required when the amount of iron lost through daily blood loss exceeds the capacity of the gastrointestinal tract to absorb oral iron preparations. (See 'Indications' below.)

• For those who have undergone gastric bypass surgery and/or subtotal gastric resection, the limited ability of the remaining stomach to oxidize ferrous to ferric iron, facilitating absorption in the distal duodenum and proximal jejunum, makes intravenous iron an especially good choice. Some patients, especially those having undergone minimally invasive procedures, such as gastric banding, may tolerate oral iron. This is less likely in Roux-en-Y or biliopancreatic diversion procedures. However, it is important to remember that all gastric bypass patients have a host of other nutritional perturbations post-operatively, and intravenous iron may simplify care.

▪ Blood transfusion — Blood transfusion should be reserved for the patient who is hemodynamically unstable because of active bleeding and/or shows evidence for end-organ ischemia. (See 'Blood transfusion' below.)

ORAL IRON THERAPY

General principles — Oral iron provides an inexpensive and effective means of restoring iron balance in a patient with iron deficiency without complicating co-morbid conditions. Frequent gastrointestinal side effects range from mild to severe constipation (especially in pregnant women), diarrhea, metallic taste, and thick, green stool. There are a few simple principles governing the use of oral iron [11,12]:

▪ Iron is not absorbed in the stomach and is absorbed best from the duodenum and proximal jejunum, where the iron transport proteins (eg, duodenal iron transporter, divalent metal transport protein and the iron export protein to blood, ferroportin) are most strongly expressed. Accordingly, enteric coated or sustained release capsules, which release iron further down in the intestinal tract, or which may be excreted intact in the stool, are inefficient sources of iron. (See "Regulation of iron balance", section on 'Duodenal iron transporter' and "Regulation of iron balance", section on 'Ferroportin'.)

▪ Iron salts should not be given with food because phosphates, phytates, and tannates in food bind the iron and impair its absorption (table 1). A number of other factors can inhibit the absorption of iron salts, including antacids, H2 receptor blockers, proton pump inhibitors, calcium-containing foods and beverages, calcium supplements, certain antibiotics (eg, quinolones, tetracycline), and the ingestion of iron along with cereals, dietary fiber, tea, coffee, eggs, or milk.

▪ Iron should be given two hours before, or four hours after, ingestion of antacids.

▪ Iron is best absorbed as the ferrous (Fe++) salt in a mildly acidic medium. As a result, we usually add a 250 mg ascorbic acid tablet or a half-glass of orange juice at the time of iron administration to enhance the degree of iron absorption.

▪ The iron preparation used should be based upon cost and effectiveness with minimal side effects. The least expensive preparation is ferrous sulfate; each tablet contains 325 mg of iron salts, of which 65 mg is elemental iron [13].

▪ Gastrointestinal tract symptoms (eg, abdominal discomfort, nausea/vomiting, diarrhea/constipation) suffered by some patients seem to be directly related to the amount of elemental iron ingested [14]. Thus, the reported low incidence of side effects for some preparations can be explained by their low elemental iron content. As examples, one tablet of iron bis-glycinate (Ferrochel, Gentle Iron) contains 27 mg of elemental iron, while a 325 mg tablet of ferrous gluconate contains 36 mg of elemental iron. Both of these preparations contain significantly less elemental iron than a 325 mg tablet of ferrous sulfate (65 mg).

▪ Patients with persistent gastric intolerance to oral iron tablets may tolerate ferrous sulfate elixir, which provides 44 mg of elemental iron per 5 mL. Patients can titrate the dose up or down to the level at which the gastrointestinal symptoms become acceptable.

Choice of preparation — The most appropriate oral iron therapy is use of a tablet containing ferrous salts, such as:

▪ Ferrous fumarate — 106 mg elemental iron/tablet

▪ Ferrous sulfate — 65 mg elemental iron/tablet

▪ Ferrous gluconate — 28 to 36 mg iron/tablet

The recommended oral daily dose for the treatment of iron deficiency in adults is in the range of 150 to 200 mg/day of elemental iron. As an example, a single 325 mg ferrous sulfate tablet taken orally three times daily between meals provides an oral dose of 195 mg of elemental iron per day. There is no evidence that one of the above iron preparations is more effective than another for this purpose.

A large number of other oral iron preparations are available. They are generally more expensive than those described above and some may be poorly absorbed (eg, enteric coated, sustained release preparations).

Dosing in older adults — Appropriate dosing of iron for older adults with iron deficiency anemia is unclear. In a randomized study in 90 iron deficient hospitalized patients >80 years of age, daily doses of 15, 50, or 150 mg of elemental iron for two months were equally effective in raising hemoglobin and ferritin concentrations, while adverse side effects were significantly more common at the higher iron doses [14].

In our practice we treat iron deficiency in older adults by using 10 mL of iron sulfate elixir once daily (elemental iron content 88 mg) mixed in one-fifth of a glass of orange juice and taken 30 minutes before breakfast. The dose of elixir can be reduced to 5 mL if the 10 mL dose causes irritation. Similarly, a 50 or 100 mg tablet of ascorbic acid can be substituted for the orange juice.

Expected response — An effective regimen for the treatment of uncomplicated iron deficiency with oral iron preparations should lead to the following responses:

▪ If pagophagia (pica for ice) or restless leg syndrome is present, it often disappears almost as soon as oral or intravenous iron therapy is begun, well before there are any observable hematologic changes such as reticulocyte response. (See "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Pica and pagophagia'.)

▪ The patient will note an improved feeling of well-being within the first few days of treatment.

▪ In patients with moderate to severe anemia, a modest reticulocytosis will be seen, maximal in approximately 7 to 10 days. Patients with mild anemia may have little or no reticulocytosis.

▪ The hemoglobin concentration will rise slowly, usually beginning after approximately one to two weeks of treatment, and will rise approximately 2 g/dL over the ensuing three weeks. The hemoglobin deficit should be halved by approximately one month, and the hemoglobin level should return to normal by six to eight weeks.

▪ Typically, papillation of the tongue is decreased in patients with iron deficiency and can be used as a gauge of duration of symptoms. Classically, loss of papillae begins at the tip and lateral borders, and moves posteriorly and centrally. Following iron repletion, a rapid correction (weeks to months) is observed.

Side effects — Estimates are that up to 50 percent of patients complain of nausea, constipation, diarrhea, epigastric distress and/or vomiting after taking various oral iron preparations [15]. There are a number of treatment options for such patients:

▪ The patient may take an iron preparation containing a smaller dose of elemental iron (eg, switching from ferrous sulfate to ferrous gluconate), or may switch from a tablet to a liquid preparation, the dose of which (44 mg elemental iron per 5 mL) can be easily titrated by the patient (see 'General principles' above).

▪ The patient may slowly increase the dose from one tablet per day to the recommended three times per day, as tolerated.

▪ The iron may be taken with meals, although this will decrease absorption somewhat.

However, with the advent of parenteral iron formulations with more favorable toxicity profiles, the early use of intravenous iron should be considered in those intolerant to the use of oral iron preparations (see 'Parenteral iron therapy' below).

Duration of treatment — There is disagreement as to how long to continue oral iron therapy:

▪ Some physicians stop treatment with iron when the hemoglobin level becomes normal, so that further blood loss will cause anemia and alert the patient and physician to the return of the problem which caused the iron deficiency in the first place.

▪ Others believe that it is wise to treat for at least six months after the hemoglobin has normalized, in order to replenish iron stores.

Our practice is to individualize the duration of iron replacement. As an example, it makes sense to fully replenish iron stores in a patient who became iron deficient as a consequence of multiple pregnancies. On the other hand, we stop therapy once the hemoglobin concentration is normalized in a patient who has occult gastrointestinal bleeding. In this latter setting, the return of iron deficiency is an important clue that bleeding has recurred.

Failure to respond to oral iron therapy — On occasion, a patient may not respond to oral iron therapy. The potential causes for this situation include the following (table 2):

▪ Incorrect diagnosis (eg, thalassemia, myelodysplastic syndrome)

▪ Patient is non-adherent

▪ Presence of a coexisting disease or treatment interfering with response (eg, elevated hepcidin levels [9], renal failure, treatment with erythropoietin and/or cancer chemotherapy). Failure of response to oral iron therapy in these settings does not rule out the presence of iron deficiency, as some will respond to treatment with parenteral iron. (See 'Indications' below.)

▪ Medication is not being absorbed for physical reasons (eg, enteric coated tablets, concomitant use of antacids)

▪ Iron (blood) loss or need is in excess of the amount ingested (eg, severe continuous GI bleeding, dialysis patient, idiopathic pulmonary hemosiderosis). (See "Idiopathic pulmonary hemosiderosis" and "Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

▪ The patient has acquired malabsorption for iron. In one study, for example, refractoriness to oral iron treatment was noted in all patients with celiac disease and approximately 70 percent of those with autoimmune atrophic gastritis or Helicobacter pylori infection [16]. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Iron deficiency' and "Metaplastic (chronic) atrophic gastritis", section on 'Helicobacter pylori' and "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Oral iron absorption test'.)

▪ The patient has an inherited condition associated with iron deficiency anemia and a failure to respond to treatment with oral iron (IRIDA). (See "Regulation of iron balance", section on 'Iron-refractory iron deficiency anemia'.)

The appropriate treatment depends upon the cause for failure to respond.

Pregnancy — Standard treatment of iron deficiency in pregnancy is the same as that in nonpregnant, postpartum, premenopausal, and postmenopausal women. However, in the pregnant patient, bloating and constipation are common problems due to high progesterone levels and the increasing pressure of the gravid uterus on the rectum. (See "Maternal gastrointestinal tract adaptation to pregnancy", section on 'Bloating and constipation'.)

Such side effects can be exacerbated by treatment with oral iron, and can be partially managed by reducing the amount of iron given and/or modifying the patient's diet, both of which require patient adherence. Furthermore, up to 70 percent of pregnant women to whom oral iron is prescribed report adverse events [17]. While numerous publications have shown the safety and efficacy of parenteral iron in this setting [18-27], its use in pregnancy is sporadic at best and is hindered by the fact that no parenteral iron preparation has been given an FDA category “A” rating for use in pregnancy (ie, controlled human studies show no risk) (table 3).

Nevertheless, a number of observations suggest the safety of intravenous iron in pregnant women:

▪ In a series of 1266 infusions of low molecular weight iron dextran (1 gram infused over one hour) given to 888 patients, 162 of whom were pregnant, no severe adverse events were noted [28].

▪ In our practice, we routinely administer 1000 mg of low molecular weight iron dextran in one hour to iron deficient pregnant women whether or not they are oral iron intolerant [24]. Although this agent has an FDA category “C” rating in pregnancy (table 3), in over 1000 treated subjects, no serious adverse effects have been observed.  

Given the preponderance of published evidence on the safety of intravenous iron in the pregnant patient, we believe that the failure to use intravenous iron in this population appears to represent an unmet clinical need. From the standpoint of the developing fetus, a more liberal use of IV iron in pregnancy will likely minimize the chance that the neonate of an iron deficient woman will also be iron deficient, especially in view of evidence that iron deficient neonates not only have delayed growth and development, but also an increase in behavioral problems later in childhood [29].

PARENTERAL IRON THERAPY

Indications — There are a number of indications for the use of parenteral, rather than oral, iron preparations. These are discussed below. Given the safety and efficacy of IV iron in a broad spectrum of diseases associated with iron deficiency, the current paradigm that oral iron is first line therapy should be reconsidered [30].

Excessive continuing blood loss — Currently, parenteral iron is most often used in iron deficient patients whose level of continued bleeding, usually gastrointestinal or menstrual, exceeds the ability of the gastrointestinal tract to absorb iron. As an example, in one study the maximum amount of iron capable of being absorbed from oral iron preparations was found to be 25 mg/day [10], the amount of iron in 25 mL of packed red cells or approximately 60 mL of whole blood. Accordingly, oral iron therapy alone would not expected to be able to keep up with chronic blood loss averaging ≥25 mL/day of packed red cells or a transfusion requirement of one unit of packed red cells every 8 to 10 days.

Inflammatory bowel disease — Many patients with inflammatory bowel disease (IBD) and iron deficiency have severe intolerance to oral iron preparations, which may also worsen IBD disease activity. (See "Nutrient deficiencies in inflammatory bowel disease", section on 'Iron'.)

Further, unlike oral iron, IV iron is able to partially overcome the iron restricted erythropoiesis associated with inflammation. Numerous studies in the United States and other countries have demonstrated the safety and efficacy of iron sucrose, LMW iron dextran, ferumoxytol, and ferric carboxymaltose in patients with inflammatory bowel disease [3,31,32]. (See 'Treatment issues' above.)

It has therefore been suggested that intravenous, rather than oral, iron should be considered in patients with IBD for the following scenarios [33]:

▪ Anemia and unresponsiveness to or intolerance of oral iron

▪ Need for a quick recovery from anemia

▪ Adjuvant use of erythropoietin

Chronic kidney disease — IV iron is the current standard in both dialysis and non-dialysis associated chronic kidney disease patients for multiple reasons, including ongoing blood loss associated with the procedure, the need for adequate iron to respond to the administration of erythropoietic stimulating agents, as well as the frequent inability of these patients to utilize iron administered orally [4,5]. (See "Iron balance in non-dialysis, peritoneal dialysis, and home hemodialysis patients", section on 'Indications for oral versus intravenous iron therapy'.)

Use in cancer patients — A large number of prospective studies support the observation that IV iron, unlike oral iron, synergizes with erythropoiesis-stimulating agents (eg, erythropoietin, darbepoetin) therapy in anemic cancer patients both on and off chemotherapy [8]. This subject is discussed in detail separately. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Iron monitoring and supplementation'.)

There is limited information on the efficacy of IV iron in anemic cancer patients receiving chemotherapy in the absence of treatment with erythropoiesis-stimulating agents [8,34,35]. An observational study in anemic cancer patients receiving IV iron (ferric carboxymaltose, median dose 1000 mg of elemental iron) indicated that patients with baseline hemoglobin levels up to 11.0 g/dL and serum ferritin levels up to 500 ng/mL responded to treatment with an increase in hemoglobin and a reduction in the need for red cell transfusions [36]. Benefit was also noted for those with ferritin levels >500 ng/mL if transferrin saturation was ................
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