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Jan B. Wade · #1 (**permalink**) 11-08-2005, 09:22 AM

The Management of Anemia
US Pharm. 2005;10:53-63.

Anemia is a significant health risk worldwide.1 It is estimated that 3.5 million people in the United States, including 20% of premenopausal women, have the disorder.1 In second and third world countries, the death rate is 100% for some forms of anemia.1 In addition, the condition is one of the most underdiagnosed in the U.S.; it is estimated that millions of people are unaware that they have anemia and are currently not receiving treatment.2 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.3 As a result, individuals with anemia may be asymptomatic. Anemia has many serious implications, including cardiovascular disease, and ignoring its symptoms is a serious error.2,4 This article is the first in a two-part series that will describe the pathophysiology, symptoms, diagnosis, and treatment of anemia.

Etiology
Anemia is a term used to describe a myriad of complex signs and symptoms, which may render the condition difficult to diagnose.4 A number of factors, including blood loss, nutritional deficits, decreased or impaired production of RBCs, and RBC destruction known as hemolysis can cause anemia.4,5 These faulty mechanisms result in a decrease in the oxygen-carrying capacity of the blood.2 Clinically, this decrease in oxygen (i.e, tissue hypoxia) can cause cardiovascular and pulmonary compensatory responses that can indicate the severity and duration of the hypoxia.4

The human body can form a mature RBC in approximately 10 days. Through a process known as erythropoiesis, a stem cell is produced in the bone marrow of vertebrae, ribs, sternum, clavicle, the iliac crest, and the proximal epiphyses of the long bones in adults. The stem cell is eventually released into the circulation to develop into a mature RBC (i.e., erythrocyte).2 During the process, hemoglobin and iron are incorporated into the cell.2

There are many overlapping factors to consider when determining the cause of anemia.3 Such factors include dietary iron deficiency or the absence of substances such as ascorbate, amino acids, and succinate that favor iron absorption.3 The presence of compounds that limit iron absorption, such as phytates, oxalates, excess phosphates, and tannates, or a lack of iron absorption due to gastrointestinal disorders, malabsorption, or gastrectomy should be considered.3 Iron deficiency may also be due to blood loss from menstruation, pregnancy, parturition, lactation, or chronic bleeding of the gastrointestinal tract due to various conditions (e.g., peptic ulcer, hemorrhoids, cancer, colonic ulceration, parasitic infection, including hookworms).3 Abnormalities in iron storage, deficiency in the release of iron from the reticuloendothelial system, inhibition of iron transport to hemoglobin (i.e., lead toxicity), and rare genetic conditions can cause anemia.3 Bleeding from the genitourinary tract, including that from uterine fibroids, is also a factor.3

Signs and Symptoms
Since anemia may result in only a few symptoms, due to the gradual progression of the disease, the condition is hard to diagnose.3 Signs and symptoms alone do not reflect the severity or provide information about the cause of the disease.4

Signs and symptoms associated with iron deficiency anemia and nutritional deficit anemia include pallor, rapid exhaustion, headache, dyspnea, angina, fatigue, vertigo, rapid heart rate, irritability, amenorrhea, gastrointestinal complaints, pale conjunctiva, and pica (a craving for unnatural foods such as dirt and chalk).3-5 Anemia can cause abnormalities involving proliferative tissues, especially mucous membranes and fingernails.3 Nails may become thin, flat, and concave in the latter stages.5,6 Angular stomatitis, as well as burning and redness of the tongue, which eventually becomes smooth and waxy in appearance, may also occur.5

Subclinical consequences of iron deficiency include compromised immune functions, impaired cognitive development, decreased reproductive functions, and decreased work capacity and performance.1 Craving and consuming large quantities of ice (i.e., pagophagia) can also a result from iron deficiency.7 In severe cases, jaundice and splenomegaly can occur. In the most severe cases, anemia can cause heart failure or shock.4 These signs and symptoms indicate that the body is trying to compensate for the hypoxia.6

Types of Anemia
Many forms of anemia exist, and each has its own cause (table 1). Production deficit anemias can be diagnosed through examination of cellular changes in the erythrocytes.4 Microcytic, hypochromic RBCs provide evidence of a defect in heme or globin synthesis.4 Iron deficiency causes RBCs to become microcytic (i.e, decreased mean corpuscular volume [MCV]) and hypochromic (i.e., decreased mean corpuscular hemoglobin concentration [MCHC]).5,8 Microcytic, hypochromic RBCs can be found in patients with chronic disease and thalassemia.4 Normochromic, normocytic anemias that have defective production present infer a hypoproliferative or hypoplastic mechanism.4

Graph - http://www.uspharmacist.com/publish/images/8_1593_0.jpg

Macrocytic, megaloblastic anemias are characterized by large RBCs or macrocytes and suggest a defect in DNA synthesis. A defect in the B12 or folate metabolism usually causes of this type of anemia.4 It may also be caused by cytoreductive chemotherapeutic agents interfering with DNA synthesis.4 Combined anemias can be present and can cause changes in the clinical picture, making it harder to recognize the disorder.9

Blood loss anemia leading to iron deficiency is the most common anemia, affecting 10% to 20% of the world population.5 Even a small amount of continuous blood loss causes less iron to be recycled in the body, preventing the adequate production of hemoglobin.6 This should always be considered during patient examinations.4

After malignancy, hereditary disorders (e.g., telangiectasia), and anemia of parasitic origin have been ruled out, the gastrointestinal system should be examined as a route of blood loss. Menstrual blood loss, the most common cause of iron deficiency, should be considered in women.5,7

Iron Deficiency Anemia
By attaching itself to a protein called transferrin, iron is transported through the bloodstream.5 Transferrin levels are elevated when there is an iron deficiency and are diminished when anemia due to a chronic disease exists.4 Measuring transferrin infers iron-binding capacity and is also used to determine the bodyÃŒs iron stores.5 Ferritin, an iron storage glycoprotein, is found in the bloodstream and tissues such as bone, liver, spleen, and muscle.4,5 Ferritin levels parallel the storage of iron in the body and can be used as an indirect measurement of the tissue supplies of iron, as well as the bodyÃŒs iron stores.4,5

Serum ferritin is the most sensitive measurement of iron and only falls when a true iron deficiency is present.5 Iron deficiency anemia is best diagnosed by checking serum ferritin levels.1 If lower than 50 mcg/L, the soluble transferrin receptor level, receptors for transferrin, which are the docking site for iron, should be measured.1 When iron levels are normal, the synthesis of the receptors is reduced and ferritin production is increased.10 If the iron becomes deficient, the receptor numbers are increased and ferritin concentrations are reduced to favor uptaking iron and preventing storage.10 If the number of receptors is greater than 28, iron deficiency anemia is likely.1

With chronic inflammation and chronic disorders, there may be a defective release of iron into the plasma from the iron stores. This is not considered a true iron deficiency anemia, but excess iron can have harmful effects on the human body.5,11 Free iron greatly increases nonspecific oxidation reactions involved in free radical degenerative effects.11 Such damage interferes with the action of nitric oxide.12 In addition, iron oxidizes low-density lipoprotein cholesterol, which can harm the arteries and heart. High iron stores have been linked to an increased risk of myocardial infarction.12 Since elevated ferritin levels occur in these iron overload states or during hepatocellular injury, acute infection, or inflammatory reaction, they should never be treated with iron supplementation.4,5,12

Iron deficiency anemia can also be caused by faulty iron absorption and/or deficiency of several vitamins and minerals required for iron absorption and utilization.5 Iron absorption is decreased by carbonates, tannates, phosphates, phytates, and oxalates by forming insoluble complexes with these substances.3,7 If adequate dietary calcium is present, complexes form between the calcium and these substances, making them unable to react with the iron.3 Antacids such as aluminum hydroxide and magnesium hydroxide also decrease absorption of iron.3,7 Increased intestinal motility reduces iron absorption.7

The levels of folic acid, copper, and vitamins B12, B6, B1, and C must also be considered.5 Stomach acid (i.e., HCl) must be present for iron absorption. Iron deficiency can result from medications that affect stomach acid secretion.1,5 About 70% to 99% of nutritional iron is excreted in the stool, depending on the existing stores of iron.5 One third of iron in the body is stored in various tissues.5 The remaining two thirds is found in functional forms including hemoglobin and RBCs.5 Most of the bodyÃŒs iron is in the form of hemoglobin, and the absorption of iron is greatly enhanced when hemoglobin stores are low.5 Iron deficiency can also cause a decrease in 25-hydroxy vitamin D, possibly by impairing small intestine absorption.11 Anemia can result from an increased requirement for iron, which exists during puberty, pregnancy, and lactation and in infancy, when there exists a rapidly growing blood volume.5

RBC survival is 120 days, and complete cessation of production will result in a decline of about 10% per week of the control value.4 When those values fall at a rate greater than 10% without hemorrhage, hemolysis is established as a causative factor.4

Treatment

Treatment for anemia ranges from supplementation to medical procedures. The underlying cause of anemia should be treated and the patientÃŒs diet should be improved.5 Treatment goals include management of the disorder, restoration of normal hemoglobin and MCV levels, and replenishing iron stores.9 A healthy diet and nutritional supplements can help prevent anemia.

Conclusion
Anemia is a grossly underdiagnosed condition. The community pharmacist is in a unique position of being able to both advise patients and educate the public about preventative care. For this reason, the pharmacist should be well versed in recognizing drugs that may be contributory and subtle, physical changes that may signal anemia. Pharmacists can administer fingernail and tongue analyses to identify individuals who should ask their health care practitioners for a blood test.

In the next article, nutritional supplementation and treatment considerations for anemia will be examined. The role of pharmacists in assisting patients with the condition will also be discussed.

To comment on this article, contact editor@uspharmacist.com.

REFERENCES
1. Segala M. Disease Prevention and Treatment. 4th ed. Hollywood, FL: Life Extension Media; 2003.

2. Online Continuing Education. Changing Paradigms in Anemia Management. Available at: www.powerpak.com/print.asp?page=courses/3101/lesson.htm.

3. Bhagavan NV. Medical Biochemistry. Boston, MA: Jones and Bartlett Publishers; 1992.

4. Berkow R, Fletcher A. Merck Manual Vol. 1 General Medicine. 15th ed. Rahway, NJ: Merck, Sharp and Dohme Research Laboratories; 1992.

5. Marz RB. Medical Nutrition from Marz. 2nd ed. Portland, OR: Omnipress; 1999.

6. Gould BE. Pathophysiology for the Health Professions. 2nd ed. New York, NY: WB Saunders Company; 2002.

7. Pelton R, LaValle JB, Hawkins EB, et al. Drug-Induced Nutrient Depletion Handbook. 2nd ed. Cincinnati, OH: Natural Health Resources; 2001.

8. Robbins A. Basic Pathology. Philadelphia: WB Saunders Company; 1976.

9. Goddard AF, McIntyre AS, Scott BB, et al. Guidelines for the management of iron deficiency anemia. Gut. 2000;46(suppl 4):iv1Ã’iv5.

10. Hardman JG, Limbird LE, Molinoff PB, et al. Goodman and GilmanÃŒs The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw Hill Health Professions Division; 1996.

11. Bradley JA, Lord RS. Laboratory Evaluations in Molecular Medicine.Norcross, GA: Institute for Advances in Molecular Medicine; 2001.

12. Whitaker J. Reversing Heart Disease. USA: Warner Books; 2002.