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Am Fam Physician. 1999;59(6):1598-1604

Anemia is a prevalent condition with a variety of underlying causes. Once the etiology has been established, many forms of anemia can be easily managed by the family physician. Iron deficiency, the most common form of anemia, may be treated orally or, rarely, parenterally. Vitamin B12 deficiency has traditionally been treated with intramuscular injections, although oral and intranasal preparations are also available. The treatment of folate deficiency is straightforward, relying on oral supplements. Folic acid supplementation is also recommended for women of child-bearing age to reduce their risk of neural tube defects. Current research focuses on folate's role in reducing the risk of premature cardiovascular disease.

Anemia is a common clinical syndrome frequently diagnosed and managed by the family physician. The prevalence of anemia in the United States has been reported to be about 29 to 30 cases per 1,000 females of all ages and six cases per 1,000 males under the age of 45, rising to a peak of 18.5 cases per 1,000 men over age 75.1
Anemia is defined as a reduction below normal in the total red blood cell volume (hematocrit) or in the concentration of blood hemoglobin.2 The normal values for hematocrit and hemoglobin vary with age and sex (Table 1).2 Proper management of the patient with anemia requires a precise etiologic diagnosis. Published algorithms can assist the physician in determining the cause of the anemia.3 Deficiencies of iron, vitamin B12 and folic acid are among the most common causes. These forms of anemia can be readily managed in an ambulatory setting.
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Iron

Iron deficiency is the most common cause of anemia worldwide.2 In children, the deficiency is typically caused by diet.4 In adults, the cause should be considered to be a result of chronic blood loss until a definitive diagnosis is established. Once the underlying cause of iron deficiency has been determined, iron replacement therapy can be initiated. Iron is available in oral and parenteral forms.
Oral iron preparations are available in both ferrous and ferric states. Ferrous salts are absorbed much more readily and are generally preferred.5 Commonly available oral preparations (Table 2) include ferrous sulfate, ferrous gluconate and ferrous fumarate (Hemocyte). All three forms are well absorbed but differ in elemental iron content. Ferrous sulfate is the least expensive and most commonly used oral iron supplement.
PreparationElemental iron (%)Typical dosageElemental iron per doseCost (generic)*
Ferrous sulfate20325 mg three times daily65 mg$1.33 to 2.42
Ferrous sulfate, exsiccated (Feosol)30200 mg three times daily65 mg6.94
Ferrous gluconate12325 mg three times daily36 mg1.68 to 2.16
Ferrous fumarate (Hemocyte)33325 mg twice daily106 mg9.00 (1.68 to 2.93)
For iron replacement therapy, most authorities recommend a dosage equivalent to 150 to 200 mg of elemental iron per day.5,6 However, recent investigations have suggested that elemental iron in dosages as low as 60 mg once or twice weekly is beneficial in selected populations.7,8 Further research is needed to determine the optimal dosing schedule for iron replacement therapy.
A standard daily dosage of 325 mg of ferrous sulfate, in three divided doses, will provide the necessary elemental iron for patients receiving replacement therapy. Hematocrit levels should show improvement within one to two months of initiation of therapy; however, the serum ferritin level is a more accurate measure of total body iron stores. Adequate iron replacement has typically occurred when the serum ferritin level reaches 50 μg per L (8.9 μmol per L).911 Depending on the cause and severity of the anemia, and on whether there is continuing blood loss, replacement of low iron stores usually requires four to six months of iron supplementation. Yet one recent study showed a benefit from replacement therapy persisting for two years.12 In patients with continuing iron requirements, a daily dosage of 325 mg of ferrous sulfate may be necessary for maintenance therapy. This is, of course, dependent on the amount of iron in the patient's diet.
Side effects from oral iron replacement therapy are common in most patients. They are mostly gastrointestinal in origin and include nausea, constipation, diarrhea and abdominal pain. To minimize side effects, iron supplements should be taken with food; however, this may decrease iron absorption by as much as 40 to 66 percent.5 Changing to a different iron salt or to a controlled-release preparation13 may also reduce side effects. Nevertheless, 10 to 20 percent of patients discontinue iron supplementation because of side effects.
For optimum delivery, oral iron supplements must dissolve rapidly in the stomach so that the iron can be absorbed in the duodenum and upper jejunum. Enteric-coated preparations are ineffective since they do not dissolve in the stomach.13 Drug interactions may also occur in patients receiving oral iron supplementation, resulting in reduced iron absorption or interference with other medications (Table 3).5
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A variety of products that contain combinations of iron, vitamin B12, folate and other nutrients are available. Use of these products is strongly discouraged, except in patients with nutritional anemias related to very poor diets or malnutrition.14 Even in these patients, use of more specific replacement therapies is preferable. Vitamin C (ascorbic acid) has been shown to enhance iron absorption, which has led to the creation of combination products that include iron and vitamin C. In practice, however, the additional amount of iron absorbed with this combination product is rarely clinically useful and does not justify the higher cost.14 Another recent study15 has shown zinc deficiency to be a contributing factor to iron deficiency anemia in female endurance runners, although further study will be needed to fully explain the clinical significance of this relationship.
Use of iron preparations (or any hematinic agents) for empiric therapy in patients with undifferentiated symptoms is inappropriate. In many instances, this practice may be detrimental to the patient. For example, iron administration will aggravate the condition of patients with undiagnosed hemochromatosis.16 The use of folic acid in patients with undiagnosed vitamin B12 deficiency will produce transient hematologic improvements but will mask the clinical symptoms of vitamin B12 deficiency, allowing neurologic deterioration to continue.17
When treating patients with documented iron deficiency anemia who do not respond to oral replacement therapy, the physician should try to identify the cause of the resistance to iron. Potential causes include continuing blood loss, ineffective intake and ineffective absorption (Table 4).18 Continuing blood loss may be overt (e.g., menstruation, hemorrhoids) or occult (e.g., gastrointestinal malignancies, intestinal parasites, side effects of nonsteroidal anti-inflammatory drugs). These sources of blood loss should be assessed in the initial evaluation of the patient with iron deficiency anemia.
Continuing blood loss
Menstruation
Bleeding hemorrhoids
Occult malignancy (especially gastrointestinal)
NSAID use and gastrointestinal bleeding
Intestinal parasites
Ineffective iron intake
Poor compliance
Gastrointestinal side effects
Acid reduction therapy
Ineffective iron absorption
Malabsorption states
Celiac disease
Crohn's disease
Pernicious anemia
Gastric surgery
Ineffective iron intake may be the result of poor compliance, often related to the frequent gastrointestinal side effects of oral iron. Iron uptake and absorption may be impaired by the concomitant use of medications that reduce stomach acid content, including antacids, H2-receptor blockers and proton pump inhibitors.9 Caffeinated beverages, particularly tea, will also reduce iron absorption.6,19 Drugs that interact significantly with oral iron supplements are listed in Table 3.
Ineffective absorption of iron may also be the result of malabsorption states, such as those in patients with celiac disease, Crohn's disease or pernicious anemia with achlorhydria. Gastric surgery may also result in iron malabsorption. To determine whether iron malabsorption is present, serum iron levels should be measured two and four hours after the patient is given 325 mg of oral ferrous sulfate. Failure of the iron level to rise by at least 115 μg per dL (20.6 μmol per L) over the pretreatment value indicates poor iron absorption.6
If the patient does not respond adequately to oral iron supplementation, parenteral treatment with iron dextran (Infed) should be considered. Specific indications for treatment with parenteral iron include the patient's inability to tolerate oral iron supplements, noncompliance with medication, malabsorption of iron after acid reduction surgery or continued blood loss.19 The severity of anemia or the desire to correct it quickly do not justify the use of parenteral iron therapy. Regardless of the route of delivery, the red blood cell requires the same length of time to utilize the supplemental iron.20
Unpredictable absorption and local complications of intramuscular administration make the intravenous route preferable for parenteral iron treatment. Parenteral iron dextran may be administered as a single dose. The total dosage required to replenish body stores is determined by body weight and hemoglobin deficit. The dosage may be calculated using the following formula5:
Injectable iron dextran, containing 50 mg of iron per mL, is supplied in a 2-mL single-dose vial and is available to the pharmacist for an average wholesale price of $37.00.21 Adverse reactions may occur with the used of injectable iron dextran. Immediate reactions include headache, dyspnea, flushing, nausea and vomiting, fever, hypotension, seizures, urticaria, anaphylaxis and chest, abdominal or back pain. A small test dose (0.5 mL) should be given to the patient first to determine whether an anaphylactic reaction will occur.22 If the patient tolerates the test dose, the full-dosage infusion may then be given at a rate of 50 mg per minute, up to a total daily dosage of 100 mg.

Vitamin B12

Since body stores of vitamin B12 are adequate for up to five years, deficiency is generally the result of the body's prolonged failure to absorb it. Pernicious anemia, Crohn's disease and other intestinal disorders are the most frequent causes of vitamin B12 deficiency. Intramuscular, oral or intranasal preparations are available for B12 replacement (Table 5). The traditional approach to treatment consists of intramuscular injections of cyanocobalamin. In patients with severe vitamin B12 deficiency, daily injections of 1,000 μg of cyanocobalamin are recommended for five days, followed by weekly injections for four weeks.23 Cyanocobalamin injections are well tolerated and rarely produce side effects. Hematologic improvement should begin within five to seven days, and the deficiency should resolve after three to four weeks of treatment. However, six months of therapy or longer will be required for signs of improvement in the neurologic manifestations of vitamin B12 deficiency. Complete or partial resolution of neurologic symptoms occurs in as many as 80 percent of patients.24 Neurologic improvement is less likely to occur in patients with severe or longstanding deficiency, and in patients whose accompanying anemia is less severe.
PreparationDosageCost*
Cyanocobalamin tablets1,000 μg daily$ 2.87
Cyanocobalamin injection1,000 μg weekly2.88 to 5.60
Cyanocobalamin nasal gel (Nascobol)500 μg weekly67.19
Folic acid (Folvite)1 mg daily4.17
Most causes of vitamin B12 deficiency, such as pernicious anemia and postsurgical malabsorption states, are chronic. As a result, patients usually require lifetime maintenance therapy consisting of 1,000 μg injections of cyanocobalamin every one to three months25 (Table 6). To determine whether maintenance therapy is adequate, serum cobalamin levels should be measured. The physician may want to consider serial measurement of cobalamin levels, since the neurologic symptoms of vitamin B12 deficiency do not consistently correlate with the severity of the anemia.24,26 However, elevated serum homocysteine or urinary methylmalonic acid levels may be more sensitive indicators of27 vitamin B12 deficiency27.
Route of administrationReplacement therapyMaintenance therapy
Intramuscular1,000 μg daily for five days, then 1,000 mg weekly for four weeks1,000 μg every one to three months
Oral1,000 to 2,000 μg daily25 to 100 μg daily25
Intranasal1,500 μg weekly for three to four weeks*500 μg weekly
Oral and intranasal preparations of vitamin B12 are also available. These routes of administration were not previously considered practical.28 However, patients with pernicious anemia will absorb 1 to 2 percent of orally ingested cobalamin without the need for intrinsic factor.23 Treating these patients with high oral dosages of vitamin B12, such as 1,000 to 2,000 μg daily, may be an alternative to parenteral therapy. Combination products containing vitamin B12 and intrinsic factor are available but are not readily absorbed. These preparations frequently induce allergic sensitization, and their use is not recommended.14
An intranasal gel containing cyanocobalamin (Nascobol) has recently been labeled for maintenance therapy of patients in hematologic remission after intramuscular vitamin B12 therapy for a variety of deficiency states. Administration of this product once weekly provides a 500-μg dose of cyanocobalamin. The patient's hematologic parameters must be within normal limits at initiation of therapy and should be monitored very closely throughout treatment. Preliminary reports suggest that intranasal cyanocobalamin may also be effective as replacement therapy in patients with vitamin B12 deficiency, although further study is needed to confirm its long-term effectiveness.29

Folate

Folate deficiency is characterized by megaloblastic anemia and low serum folate levels. Effective management of folate deficiency requires understanding its cause. Most patients with folate deficiency have inadequate intake, increased folate requirements, or both. Drug therapy with folate antagonists such as methotrexate (Rheumatrex), pyrimethamine (Daraprim), trimethoprim (Proloprim) or triamterene (Dyrenium) may also lead to folate deficiency. Treatment of folate deficiency is straightforward. In the absence of a folate malabsorption state, a once-daily dosage of 1 mg of folic acid given orally will replenish body stores in about three weeks30 (Table 5).
Folate supplementation is also recommended for women of child-bearing age to reduce the incidence of fetal neural tube defects. Current recommendations include initiating folic acid supplementation at a dosage of 0.4 mg daily before conception. Most prenatal vitamins contain this amount of folic acid. Women who have previously given birth to a child with a neural tube defect should take 4 to 5 mg of folic acid daily.31 It is believed that higher dosages do not provide any additional protection against neural tube defects.32
Research is currently underway to determine whether folic acid supplementation may reduce the risk of premature atherosclerotic cardiovascular disease.33 Elevated serum homocysteine levels are associated with an increased risk for myocardial infarction,34 stroke35 and, possibly, deep venous thrombosis.36 It remains unclear whether an elevated serum homocysteine level is directly involved in the pathogenesis of these events or merely a marker for potential cardiovascular disease. If an elevated homocysteine level is found to be associated with the atherosclerotic process, folic acid supplementation could reduce these levels, thereby reducing the risk of adverse cardiovascular events.37
The opportunity to decrease the incidence of neural tube defects and the theoretic possibility of reducing the risk of cardiovascular disease has led some nutrition authorities to recommend routine folic acid fortification of bread and other food products.31 However, because the use of folic acid supplementation partially corrects the hematologic abnormalities of vitamin B12 deficiency but not the associated neurologic deterioration,10 other experts have recommended that all foods fortified with folic acid also include vitamin B12 supplementation38.

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