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IRON DEFICIENCY ANEMIANouf Aloudah

April 13, 2009

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EPIDEMIOLOGY

Iron deficiency is the most common nutritional deficiency in developing and developed countries.

More than 500 million people worldwide are estimated to have IDA.

Data from NHANES III indicates 1% to 2% of adult in the United States have IDA.

Prevalence data vary because screening uses a simple Hb test, arbitrary normals are used, and selection of samples in population surveys tends to lead to errors.

The normal ranges for Hb and Hct are so wide that a patient may lose up to 15% of RBC mass and still have a Hct within the normal range.

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ETIOLOGY

Iron deficiency results from prolonged negative iron balance or failure to meet increased physiologic iron need.

The onset of iron deficiency depends on an individual's initial iron stores and balance between iron absorption and loss.

Multiple etiologic factors usually are involved. Certain groups at higher risk for iron deficiency include

children younger than 2 years, adolescent girls, pregnant females, and elderly older than 65 years

In less industrialized nations, the risks for developing IDA are largely related to dietary factors. Diets limited in meat or fresh fruits and vegetables or diets high in substances that form complexes with iron may result in IDA

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ETIOLOGY

Malabsorptive syndromes also may cause IDA. Situations that increase the demand for iron are frequent blood donations, participation in endurance sports, menstruation, pregnancy and lactation, infancy,

and adolescence. Iron deficiency in pregnant women is so common

that the Centers for Disease Control and Prevention (CDC) guidelines recommend initiation of low-dose iron supplements (30 mg/day) at the woman's first prenatal visit for primary prevention of IDA

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ETIOLOGY

At diagnosis, the cause of IDA must be considered a consequence of blood loss until proven otherwise.

More than 50% of adults with IDA have some form of gastrointestinal bleeding. Blood loss may occur as a result of many disorders trauma, hemorrhoids, peptic ulcers, gastritis,

gastrointestinal malignancies, arteriovenous malformations, diverticular disease, copious menstrual flow, nosebleeds, and postpartum bleeding.

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ETIOLOGY

The possibility of multifactorial causes must always be considered. 1. Medication history, specifically regarding recent or past use of iron or hematinics, alcohol,

corticosteroids, aspirin, and nonsteroidal antiinflammatory drugs, is a vital part of the history.

2. Other possible causes of hypochromic microcytic anemia include

ACD, thalassemia, sideroblastic anemia, and heavy metal (mostly lead) poisoning.

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PATHOPHYSIOLOGY

Go and Read

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LAB FINDINGS

low serum iron and ferritin levels and high TIBC. The first apparent sign of iron deficiency is the

increased RDW, although the finding is not specific to IDA.

In the early stages of IDA, RBC size is not changed.

Low ferritin concentration is the earliest and most sensitive indicator of iron deficiency

However, ferritin may not correlate with iron stores in the bone marrow because renal or hepatic disease, malignancies, infection, or inflammatory processes may increase ferritin values.

Hb, Hct, and RBC indices usually remain normal

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LAB FINDINGS

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LAB FINDINGS

In the later stages of IDA: Hb and Hct fall below normal values microcytic hypochromic anemia develops Microcytosis may precede hypochromia, as

erythropoiesis is programmed to maintain normal Hb concentration in deference to cell size. As a result, even slightly abnormal Hb and Hct levels may indicate significant depletion of iron stores and should not be ignored. In terms of RBC indices, MCV reduction occurs earlier in iron-deficient hematopoiesis than does reduction in Hb concentration

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LAB FINDINGS

Transferrin saturation (i.e., serum iron level/TIBC) is useful for assessing IDA. Low values likely indicate IDA, although low serum transferrin saturation values also may be present in inflammatory disorders

Fortunately, the TIBC usually helps to differentiate the diagnosis in these patients: TIBC >400 mcg/dL suggests IDA, whereas values <200 mcg/dL usually represent inflammatory disease

With continued progression of IDA, anisocytosis occurs and poikilocytosis develops, as seen on peripheral blood smear and indicated by increased RDW.

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LAB FINDINGS In rare cases, a bone marrow examination is indicated

to assess bone marrow iron stores. Bone marrow examination reveals absent iron stores in

IDA. Documentation of decreased hemosiderin can confirm

the diagnosis of IDA. In microcytic anemias due to all other causes, iron

stores are detectable. Serum transferrin receptor can be used to diagnose

iron-store depletion and defects in iron delivery to the marrow.

Commercial assays are available but are not well standardized. An elevated serum transferrin receptor level would be expected in IDA and a normal level in ACD.

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TREATMENT

The severity and cause of IDA determines the approach to treatment.

Treatment is focused on replenishing iron stores. Because iron deficiency can be an early sign of other illnesses, treatment of the underlying disease may aid in the correction of iron deficiency.

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TREATMENT

Dietary Supplementation and Therapeutic Iron Preparations

Treatment of IDA usually consists of 1. dietary supplementation 2. administration of therapeutic iron preparations.

Iron is poorly absorbed from vegetables, grain products, dairy products, and eggs; it is best absorbed from meat, fish, and poultry.

Beverages have been shown to affect iron absorption. Meat, orange juice, and other ascorbic acid–rich foods should be included with meals, whereas milk and tea should be consumed in moderation between meals. In most cases of IDA, oral administration of iron therapy with soluble Fe2+ iron salts is appropriate.

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TREATMENT

Clinical Controversy Daily Fe2+ sulfate is not tolerated by all

patients and can be difficult to administer in populations of developing nations. Weekly rather than daily supplements have been used, with conflicting efficacy results. The weekly approach follows the natural pattern of mucosal cell iron turnover

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TREATMENT

Fe2+ sulfate, succinate, lactate, fumarate, glycine sulfate, glutamate, and gluconate are absorbed similarly.

The addition of copper, cobalt, molybdenum, or other minerals or hematinics provides no advantage but adds expense. The carbonyl iron may be advantageous because of lower risk for death in cases of accidental overdose

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TREATMENT

Iron is best absorbed in the reduced Fe2+ form, with maximal absorption occurring in the duodenum, primarily due to the acidic medium of the stomach.

The presence of mucopolysaccharide chelator substances prevents the iron from precipitating and maintains the iron in a soluble form

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TREATMENT

In the alkaline environment of the small intestines, iron tends to form insoluble complexes that are unavailable for absorption.

Slow-release or sustained-release iron preparations do not undergo sufficient dissolution until they reach the small intestines, which significantly reduces iron absorption and can attenuate the hematinic effects. This is especially true when enteric-coated preparations are used in achlorhydric patients.

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TREATMENT

The dose of iron replacement therapy depends on the patient's ability to tolerate the administered iron.

Tolerance of iron salts improves with a small initial dose and gradual escalation to the full dose.

In patients with IDA, the general recommendation is administration of approximately 200 mg of elemental iron daily, usually in two or three divided doses to maximize tolerability.

However, if patients cannot tolerate this daily dose of elemental iron, smaller amounts of elemental iron (e.g., single 325-mg tablet of Fe2+ sulfate) usually is sufficient to replace iron stores, albeit at a slower rate

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TREATMENT

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TREATMENT

The percentage of iron absorbed decreases progressively as the dose increases, although the absolute amount absorbed increases

Iron preferably is administered at least 1 hour before meals because food interferes with iron absorption. Many patients must take iron with food because

they experience nausea and diarrhea when iron is administered on an empty stomach.

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ADVERSE EFFECTS

gastrointestinal in nature and consist of a dark discoloration of feces, constipation or diarrhea, nausea, and vomiting.

Gastrointestinal side effects usually are dose-related and are similar among iron salts when equivalent amounts of elemental iron are administered.

Administration of smaller amounts of iron with each dose may minimize these adverse effects

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ADVERSE EFFECTS

Histamine2 blockers or proton pump inhibitors that reduce gastric acidity may impair iron absorption.

Failure to develop at least some mild gastrointestinal symptoms may suggest non-adherence.

If these side effects become intolerable, the total daily dose can be decreased to 110 to 120 mg of elemental iron, or the dose can be taken with meals. It should be noted, however, that administration of iron with meals reduces the amount of iron absorbed by more than half.

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DRUG INTERACTIONS

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FAILURE TO TREATMENT

Failure to respond to appropriate treatment regimens necessitates reevaluation of the patient's condition

"therapeutic trial of iron" approach will be used to confirm a presumptive diagnosis of IDA.

Common causes of treatment failure include poor patient adherence, inability to absorb iron,

incorrect diagnosis, continued bleeding, or a concurrent condition that impairs full reticulocyte response.

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FAILURE TO TREATMENT Even when iron deficiency is present, response may

be impaired when a coexisting cause for anemia exists.

Rarely a patient is not able to absorb iron, most often due to previous gastrectomy or celiac disease.

Malabsorption can be ruled out by the iron test, in which plasma iron levels are determined at half-hour intervals for 2 hours following the administration of 50 mg of elemental iron as liquid Fe2+ sulfate. If plasma iron levels increase by >50 mcg/dl during this

time, absorption is satisfactory. Regardless of the form of oral therapy used, treatment should

continue for 3 to 6 months after the anemia is resolved to allow for repletion of iron stores and to prevent relapse

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PARTENTERAL IRON THERAPY

When evidence of iron malabsorption or intolerance to orally administered iron is seen or long-term non-adherence is suspected, parenteral iron therapy may be warranted

Patients with significant blood loss who refuse transfusions and cannot take oral iron therapy also may require parenteral iron therapy.

Parenteral iron does not lead to a quicker hematologic response than that of oral iron. The ideal parenteral iron supplement would be safe, efficacious, and convenient and would maintain consistent patient outcomes

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PARTENTERAL IRON THERAPY

Three different parenteral iron preparations currently available

They differ in their molecular size, degradation kinetics, bioavailability, and side-effect profiles.

Although toxicity profiles of these agents differ, clinical studies indicate that each is efficacious. Most of the recent research on intravenous iron has been performed in hemodialysis patients. iron dextran sodium ferric gluconate iron sucrose

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PARTENTERAL IRON THERAPY Dextran parenteral preparations have been

associated with death due to anaphylactic reactions. These reactions may be related to immune reactions to

the iron–carbohydrate or iron–dextran complex. Another theory for the anaphylaxis is the high-molecular-weight dextran component, which may be antigenic even when not complexed to iron. The safety profile of iron is largely assessed by spontaneous reports to the Food and Drug Administration (FDA) and retrospective and open-label prospective studies.

Results of these studies suggest that Fe3+ gluconate and iron sucrose are safer than iron dextran. The concern with parenteral iron is that iron may be released too quickly and overload the ability of transferrin to bind it, leading to free iron reactions that can interfere with neutrophil function.

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PARTENTERAL IRON THERAPY

Iron dextran, a complex of Fe3+ hydroxide and the carbohydrate dextran, contains 50 mg of iron per milliliter and can be given via the intramuscular or intravenous route. Different brands of iron dextran are available and differ in their molecular weight. They are not interchangeable

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PARTENTERAL IRON THERAPY

Iron dextran must be processed by macrophages for the iron to be biologically available. The absorption and metabolism vary with the route and amount of drug given

Absorption of an intramuscular dose of iron dextran occurs in two phases

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PARTENTERAL IRON THERAPY

Total replacement doses of intravenous iron dextran have been given as a single dose, diluted in 250 to 1,000 mL normal saline or 5% dextrose in water and infused over 4 to 6 hours.

A test dose still is required. The ability to give a total dose infusion is a

benefit of iron dextran over the other parenteral iron products. Iron dextran is best utilized when smaller frequent doses of sodium ferric gluconate or iron sucrose are impractical, as with peritoneal dialysis.

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PARTENTERAL IRON THERAPY

Patients who receive total dose infusions are at higher risk for adverse reactions, such as arthralgias, myalgias, flushing, malaise, and fever.

Other adverse reactions of iron dextran include staining of the skin, pain at the injection site, allergic reactions, and rarely anaphylaxis

Patients most likely to experience adverse effects with iron dextran include individuals with a history of allergies, asthma, or inflammatory diseases. Patients with preexisting immune-mediated diseases, such as active rheumatoid arthritis or systemic lupus erythematosus, are considered at high risk for adverse reactions because of their hyperreactive immune response capabilities

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PARTENTERAL IRON THERAPY

Sodium ferric gluconate is a complex of iron bound to one gluconate and four sucrose molecules in a repeating pattern. Sodium ferric gluconate is available in an aqueous solution. No direct transfer of iron from the Fe3+ gluconate to the transferrin occurs.

It is supplied in 5-mL ampules containing 62.5 mg of elemental iron.

Sodium ferric gluconate appears to produce fewer anaphylactic reactions than does iron dextran. According to the package insert, a test dose of sodium ferric gluconate is not required. If given, a test dose is administered as 2 mL (25 mg of elemental iron) in 50 mL normal saline intravenously over 60 minutes.

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PARTENTERAL IRON THERAPY

Although sodium ferric gluconate can be administered undiluted as a slow intravenous injection (up to 12.5 mg/min), it is most commonly administered as 10 mL (125 mg of elemental iron) in 100 mL normal saline intravenously over 1 hour. Most hemodialysis patients require a minimum total of 1 g of elemental iron over eight dialysis sessions to replete their stores.

Side effects of sodium ferric gluconate include cramps, nausea, vomiting, flushing, hypotension, intense upper gastric pain, rash, and pruritus.

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PARTENTERAL IRON THERAPY

Iron sucrose is a polynuclear iron (III) hydroxide in sucrose complex.

It is available in 5-mL single-dose vials. Each vial contains 100 mg (20 mg/mL) of iron sucrose.

Following intravenous administration of iron sucrose, the iron is released directly from the circulating iron sucrose to the transferrin and is taken up by the mononuclear phagocytic system and metabolized

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PARTENTERAL IRON THERAPY

The half-life is approximately 6 hours, with a volume of distribution similar to that of iron dextran.

For adults undergoing hemodialysis, iron sucrose is administered as an intravenous dose of 100 mg one to three times per week to a total dose of 1,000 mg in 10 doses.

It can be given directly into the dialysis line by slow intravenous injection (20 mg iron [1 mL] per minute) or via infusion without the requirement for a test dose

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PARTENTERAL IRON THERAPY

For infusion, it must be diluted in normal saline (maximum 100 mL) immediately prior to use and infused over a minimum of 15 minutes.

Iron sucrose injection should not be administered concomitantly with oral iron preparations because it will reduce the absorption of oral iron

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PARTENTERAL IRON THERAPY

Adverse effects include leg cramps and hypotension.

Iron sucrose has been shown to be well tolerated but has less-than-expected efficacy at maintaining Hb >11 g/dL and transferrin saturation >25%.

Approximately 50% of patients studied had serum ferritin levels >1,100 ng/mL, which suggests iron overload. The reduced hematologic response and development of high serum ferritin levels may be due to oversaturation of transferrin and release of free iron. Varying doses of iron sucrose may not produce these results. Overall, iron sucrose has been shown to be safe and efficacious

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PARTENTERAL IRON THERAPY

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TRANSFUSIONS

Another form of treatment involves blood transfusions. The decision to manage anemia with blood transfusions is based on the evaluation of risks and benefits. Transfusion of allogeneic blood is indicated in acute situations of blood loss when hemodynamic support is needed

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EVALUATION OF THERAPEUTIC OUTCOMES

A positive response to a trial of oral iron therapy results in a modest reticulocytosis in 5 to 7 days, with an increase in Hb at a rate of approximately 2 to 4 g/dL every 3 weeks until Hb is normalized. As the Hb level approaches normal, the rate of increase slows progressively. A Hb response of <2 g/dL over a 3-week period warrants further evaluation. If the patient does not develop reticulocytosis, reevaluation of the diagnosis or iron replacement therapy is necessary

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EVALUATION OF THERAPEUTIC OUTCOMES

Iron therapy should continue for a period sufficient for complete restoration of iron stores.

Serum ferritin concentrations should return to the normal range prior to discontinuation of iron. The time interval required to accomplish this goal varies, although at least 3 to 6 months of therapy usually is warranted.

Patients with negative iron balances caused by bleeding may require iron replacement therapy for only 1 month after correction of the underlying lesion, whereas patients with recurrent negative balances may require long-term treatment with as little as 30 to 60 mg of elemental iron daily.

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EVALUATION OF THERAPEUTIC OUTCOMES

When large amounts of parenteral iron are administered, by either total dose infusion or multiple intramuscular or intravenous doses, the patient's iron status should be closely monitored.

For patients intolerant of iron dextran, ferric gluconate and iron sucrose are alternatives.

Cost, number of infusions, impact on need to transfuse, and concurrent EPO supplementation affect the choice of parenteral iron products.

Patients receiving regular intravenous iron should be monitored for clinical or laboratory evidence of iron toxicity or overload.

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EVALUATION OF THERAPEUTIC OUTCOMES

Iron overload may be indicated by abnormal hepatic function tests serum ferritin >800 ng/mL, transferrin saturation >50%. Serum ferritin and transferrin saturation should

be measured in the first week after doses of 100 to 200 mg and 2 weeks after larger intravenous iron doses.

Hb and Hct should be measured weekly, and serum iron and ferritin levels should be measured at least monthly.

Serum iron values can be obtained reliably 48 hours after intravenous dosing.

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