Anemia is one of the most underdiagnosed conditions and, if left untreated, can have many serious implications such as cardiovascular disease and compromised immune functions.1 The condition, characterized by a decrease in the size or number of red blood cells (RBCs) and/or decreased hemoglobin content, may progress slowly over months or years, during which many physiological adjustments occur. As a result, many individuals with anemia may be asymptomatic. However, several screening methods, such as a physical exam and evaluation of a patient's medication history, can identify individuals at high risk for developing this blood disorder. Iron and nutritional deficiency anemias can be treated through dietary changes, supplementation, and in some cases, medical procedures to prevent blood loss. This article is the second in a two-part series that will describe treatment considerations for iron deficiency and nutritional anemias.



Iron Deficiency Anemia

Iron deficiency is the most common cause of nutritional anemia.2 Anemia as a result of insufficient dietary intake of iron is rare in the United States, where a diet rich in meat and iron fortified foods such as cereals, flours, and bread is standard.3,4 It is more common for anemia to result from excessive iron loss caused by chronic bleeding.3 Bleeding ulcers and hemorrhoids are two of the most common reasons for blood loss. Chronically bleeding gastrointestinal (GI) lesions (scarring) can also cause poor iron absorption.3 In addition, iron deficiency anemia can result from chronic bleeding of benign polyps in the colon, colon cancer, or tumors in other parts of the body such as the kidney. Gastric and colorectal adenocarcinomas also contribute to the condition.3 In addition, iron deficiency anemia commonly occurs in 5% to 10% of menstruating women.5


Iron converts back and forth between oxidation states--the reduced (ferrous) state and its oxidized ( ferric) state--and holds or releases oxygen to function in energy production. 3 The mineral is absorbed in the ferrous state and is then reduced in the GI tract by ascorbate, succinate, and amino acids.6 Gastric acid potentiates iron absorption by aiding in the formation of soluble and absorbable ferrous chelates.6 Clinical expression of anemia results from the reduced amount of oxygen the blood can carry (tissue hypoxia) and is due to a reduced blood cell count.3 Low ferritin levels occur only in a true iron deficiency state.7


Dietary Sources of Iron
In food sources, iron exists in a ferric state chemically complexed to proteins, amino acids, organic acids, or heme.6 Heme is absorbed intact from food and is more effective than inorganic iron.6 Organ meats (especially the liver), legumes, dark green leafy vegetables, and whole grains are good dietary sources of iron.2 While molasses contains a small amount of iron, its chemical makeup has been shown to allow a more efficient absorption of iron compared to other iron-containing foods.2


For patients with iron deficiency anemia, dietary considerations should be made to avoid foods that inhibit iron absorption. For instance, drinking tea with meals can reduce iron absorption by as much as 50%.5 Iron absorption is inhibited by coffee, black and green tea, soy products, and digestive enzymes (e.g., amylase, protease, lipase).2,8


Iron Supplementation
The need for iron supplementation should be determined by a physician. Iron can be taken in many different forms, including sulfate (20% iron), gluconate (12%), fumarate (33%), glycinate (27%), and ferric ammonium citrate (16.5%).4 The average dose for the treatment of iron deficiency anemia is 200 mg/day of ferrous sulfate in three equal doses.9 This is an inexpensive and effective way to supplement the mineral.9,10 Ferrous salts are absorbed about three times as well as ferric salts.9 In addition, at least 1 g/day of buffered vitamin C aids absorption.5,11 Taurine 1 g/day may also be beneficial in treating iron deficiency.2 In pregnant women, 15 to 30 mg/day of iron is adequate for the prevention of iron deficiency anemia.9


Floradix (iron gluconate and iron-fed yeast/Flora Inc.) is a liquid iron supplement with herbs that contains 10 mg of elemental iron/2 teaspoons and may be better absorbed than other iron products. The product can produce quick results in mild to moderate anemias and is nonconstipating and easy to digest.12 Iron protein succinylate is another supplement whose absorption is not effected by H2 receptor antagonists, drugs, or food intake.3


In menstruating women, menorrhagia is usually responsible for iron deficiency anemia. Iron deficiency itself can cause menorrhagia because normal uterine tone, which contributes to the cessation of bleeding, requires an adequate supply of iron.2 To counteract continued bleeding, 100 mg/day of elemental iron can be given.5 Vitamin A should also be considered in this group to improve the absorption and utilization of iron and possibly increase serum levels of 17-beta estradiol.2 In an uncontrolled trial of 71 women with menorrhagia, 40 subjects were given vitamin A 25,000 IU twice daily for 15 days. Menstruation returned to normal in 57.5% of these women, and another 35% had a substantially diminished menstrual flow or reduction in the duration of the menses.2


Iron supplementation is best accomplished by taking the smallest amount needed to restore ferritin levels to the mid-normal range (30 to 300 ng/mL).7 Iron supplementation is indicated if ferritin levels drop below 30 ng/mL in men, 40 ng/mL in women, or 60 ng/mL in pregnant women.5 It is better to lower the dose to tolerance since the effects of food can mean one half to one third less absorption.9 The timing of iron supplements is also important since sustained high levels of red cell production require an uninterrupted supply of iron. Oral doses should be spaced equally to maintain a continuous high concentration of iron in plasma.9







It is important to note that iron interferes with the absorption of several drugs, including levothyroxine, ciprofloxacin, norfloxacin, captopril, and penicillamine (Table 1).2 These interactions can decrease absorption of thyroid products, as well as form a complex with fluoroquinolones and render them ineffective. In addition, iron products can cause GI distress such as nausea, heartburn, upper gastric discomfort, diarrhea, and constipation. Pharmacists should advise patients to take iron supplements on an empty stomach to maximize iron absorption and discourage taking supplements within two hours of certain drugs (e.g., thyroid medication, fluoroquinolones, tetracyclines). If upset stomach occurs, patients should be advised to take iron supplements with food but not within two hours of a drug that may interfere with iron absorption.5,9,13






In severe cases, iron dextran can be administered intramuscularly or intravenously.3 Transfusions are rarely indicated for iron anemia and can be dangerous due to the demand that the new blood volume puts on an already taxed heart.3



Duration of iron supplementation is determined by the rate of hemoglobin recovery and desire to create iron stores. Depending on the severity of the anemia, the red cell mass can usually be reconstituted in one to two months.9 Creating stores can take a much longer time; stores will replenish at a much slower rate after three to four months of iron replacement. Judgments should be based on patients' resolution of bleeding and ability to maintain the stores.


Patients should be reminded to follow up with their physician to determine if the need for iron supplementation still exists. Some patients mistakenly take iron supplements long after the deficiency state is corrected. Overloading the body with too much iron dramatically increases the risk of cancer, heart disease, neurological degeneration, and possibly, atherosclerosis.2,3 Iron excesses generate massive free radical reactions.3


Nutritional Deficiency Anemias
In addition to iron, several other nutritional deficiencies can contribute to or result in anemia.


Folic Acid: Folic acid deficiency is an extremely common cause of anemia.14 The vitamin is inactive in the body until it is converted to tetrahydrofolic acid.3 Folate has six important biological chemical reactions including the catabolism of histidine and the synthesis of methionine and purines.3 Formiminoglutamic acid, an intermediary ----bolite, will accumulate if folate is deficient and there is a failure to break down histidine.3 This can be measured in the serum and is a useful clinical marker for folate deficiency.3


Folic acid deficiency generally occurs in malnourished patients, especially those with alcoholism. 3 The deficiency also occurs in pregnant women, infants fed solely on cow's milk, and adults over age 60.3 Malabsorption syndromes can produce a folic acid deficiency.3 Several drugs (e.g., phenytoin, phenobarbital, primidone, isoniazid, cycloserine) can also deplete folic acid through the attenuation of folate absorption and ----bolism. 3


Folic acid is found in asparagus, broccoli, endive, spinach, and lima beans.3 The vitamin is also found in liver, dried beans, brewer's yeast, wheat bran, dark green leafy vegetables, and whole wheat bread.5 Since heat destabilizes folate, it is recommended that these foods be consumed in a state that is as minimally -----d as possible.


Treatment is based on the differential diagnosis of folic acid deficiency and should be distinguished from a B12 anemia. An oral dose of 1 to 5 mg folate is a typical treatment for this anemia. Folic acid deficiency responds quickly to oral supplementation of folic acid.3 Symptoms often improve before hematologic values return to normal.5 Folic acid is commercially available in a 5 mg/mL vial. Up to 1 mg/day of folic acid intramuscularly or subcutaneously can be given to patients with folic acid anemia.2


Vitamin B12: Vitamin B12 anemia (i.e., pernicious anemia) occurs when levels of the vitamin are low, which is usually due to an absorption problem, rather than an actual dietary deficiency.3 Vitamin B12 promotes maturation of RBCs in the bone marrow.3,13 Risk factors for this anemia include a vegetarian diet, thyroid disease, diabetes, a family history of vitamin B12 deficiency, and surgical removal of a part of the stomach that produces factors essential to the absorption of vitamin B12.3,5 B12 anemia can also result from gastric bypass surgery.3


Vitamin B12 anemia affects 10% to 15% of people over age 60.3 The condition can be diagnosed by measuring the serum level of the vitamin; the range of B12 serum levels can be between 200 and 900 pg/mL.3 This test has a wide reference range and sometimes detects cobalamin analogs that do not have any B12 activity. Therefore, this test is not very qualitative. When diagnosing vitamin B12 anemia, it is helpful to look for elevated levels of serum methylmalonic acid and homocysteine.3,5 If vitamin B12 deficiency is left untreated, it can lead to serious health conditions such as congestive heart failure, neurological problems, increased incidence of infections, and impotency in males.3


The best sources of vitamin B12 are from animal products such as beef liver, clams, salmon, lamb, lobster, tuna, beef, cheese, milk, halibut, eggs, and chicken.5 Nonanimal sources include brewer's yeast and sea vegetables (e.g., nori, walkame, arame). Micro-algaes (e.g., chlorella, spirulina) also contain B12. Super blue green algaes are the best algae source of B12.


Treatment of vitamin B12 deficiency includes supplementation of the vitamin through injection (cyanocobalamin, 1,000 mcg/mL) or through oral (methylcobalamin, 1,000 to 2,000 mcg), sublingual, or transdermal forms.3 Orally administered methylcobalamin may be considered as effective as an injection of vitamin B12 for the long-term treatment of this deficiency. Patients unable to absorb B12 should receive an injection of the vitamin. It may take two to three months for the serum concentrations to resolve with oral methylcobalamin therapy. 3 Treating the underlying condition that is causing the anemia should be considered the most important part of treatment.5


Copper: Copper deficiency can cause a microcytic anemia that may be worsened by iron supplementation. Copper is required for the proper formation of hemoglobin. When the mineral is deficient, iron cannot be released from storage sites.


Dietary sources of copper include whole grains, nuts, legumes, vegetables, and meat.2 While Western diets typically provide about 1 mg/day of copper, recommended doses of the mineral range from 2 to 4 mg. Several nutrients, including vitamin C, iron, and molybdenum, can inhibit copper absorption. Ingesting large doses of zinc can also cause a copper deficiency.


If patients with copper deficiency anemia are supplemented with iron, symptoms will worsen.15 However, if ferritin levels are not checked, it may appear that iron supplementation is necessary. Copper deficiency is an example of why proper diagnosis of anemia is necessary before iron supplementation is initiated. 5


Role of the Pharmacist
Pharmacists are positioned to evaluate, educate, and counsel patients on their health conditions and medications. To assess a patient's risk for anemia, pharmacists can perform a physical exam or ask questions about his or her diet and medication history ( table 2). Patients who are taking H2 antagonists, have GI disorders, or are pregnant are at high risk. In addition, pharmacists can counsel patients on the proper supplementation of iron, vitamin B12, and folic acid, encourage patients to follow up with their physician to determine resolution of anemia, and educate patients about potential side effects such as nutritional deficits that can occur from medication use and result in anemia.










Anemia can be diagnosed with a physical exam and blood tests including a complete blood count that measures levels of RBCs and hemoglobin in the blood. Pharmacists can provide patients with a list of drugs that deplete iron, folic acid, and vitamin B12 and conditions (e.g., gastric bypass surgery) that can contribute to anemia. This may prompt patients to be further assessed by a pharmacist and physician.


A screening method that pharmacists can use is checking for perfusion under a patient's fingernails. This can be done by depressing the fingernail and observing capillary refill. 16 The tissue underneath a person's fingernail is normally full of blood and refills within two seconds after being pressed. In a person with serious blood loss (internal or external), the tissue under the fingernail remains white and bloodless. In an anemic patient, the perfusion takes longer than two seconds, but eventually the blood returns.16 If the perfusion time is slow, the pharmacist could also check the mucosa in the lower eyelid, mouth, or gum tissue. In patients with anemia, these will also appear pale depending on the severity and the length of time that the disorder has existed. When looking at a patient's gums, the pharmacist should check the tongue for a smooth, glossy appearance. Anemia can cause a patient's tongue to be sore, which is often a primary complaint in these individuals.7


Patients found to have physical symptoms of anemia should be directed to their physician to have the condition properly diagnosed. If a patient needs iron replacement, the pharmacist is the best source for information concerning iron use. A good resource for information on products containing iron is www.factsandcomparisons.com. This site contains tables of over-the-counter (OTC) and prescription products available in the U.S. Each listing provides the dosage form and iron content of products. Pharmacists are provided with a 30-day free trial of the Web site.


Conclusion
Anemia can be a significant health risk. Pharmacists are positioned to screen patients for this sometimes hidden and undiagnosed disorder. Pharmacists can also notify the physician of the need for a blood test and recommend that ferritin levels be determined and a complete blood count be performed. Pharmacists can recommend iron products to patients who require supplementation, as many anemias can be corrected with the use of OTC products. Pharmacists should also recommend that patients receive a blood analysis in two months and follow up with their physician to determine the underlying cause of the anemia. The pharmacist can have an important role by identifying patients at high risk for anemia and encouraging these individuals to seek additional medical attention.


REFERENCES
1. Online Continuing Education. Changing Paradigms in Anemia Management. Available at: http://www.powerpak.com/print.asp?pa...101/lesson.htm. Accessed November 9, 2005.
2. Wright JV, Gaby AR. Nutritional Therapy in Medical Practice Protocols and Supporting Information. Carlisle, PA: Nutrition Seminars; 2003.
3. Segala M. Disease Prevention and Treatment. 4th ed. Hollywood, FL: Life Extension Media; 2003.
4. Pelton R, Lavalle JB, Hawkins EB, et al. Drug Induced Nutrient Depletion Handbook. 2nd ed. Cincinnati, OH: Lexi-Comp Inc; 2001.
5. Marz RB. Medical Nutrition from Marz. 2nd ed. Portland, OR: Omnipress; 1999

Iron converts back and forth between oxidation states--the reduced (ferrous) state and its oxidized ( ferric) state--and holds or releases oxygen to function in energy production. 3 The mineral is absorbed in the ferrous state and is then reduced in the GI tract by ascorbate, succinate, and amino acids.6 Gastric acid potentiates iron absorption by aiding in the formation of soluble and absorbable ferrous chelates.6 Clinical expression of anemia results from the reduced amount of oxygen the blood can carry (tissue hypoxia) and is due to a reduced blood cell count.3 Low ferritin levels occur only in a true iron deficiency state.

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