Definition and Epidemiology

Anemia is not a disease but rather a sign or symptom of an underlying disorder. Anemia is defined as a reduction in the number of red blood cells (RBCs), hemoglobin concentration, or hematocrit. In general, a hemoglobin concentration in adults below 13.6 g/dL for men or below 12 g/dL for women suggests anemia.¹ Although certain signs and symptoms are sometimes associated with anemia, the diagnosis is often based on laboratory data alone.

As one of the most common hematologic diagnoses, anemia affects people of every age group. Some types of anemia have a higher incidence in certain races and ethnicities. For example, sickle cell disease is most common in those of African ancestry, and thalassemia in people from the geographic regions of the Mediterranean, the Middle East, Southeast Asia, and parts of India and Pakistan.

Pathophysiology

Anemia is a condition in which too little oxygen is being transported to the tissues. Inadequate supplies of oxygen in the tissues produce the symptoms of anemia. There are many types of anemia with a variety of different causes. Grouping them into the categories of (1) RBC production disorders, (2) RBC destruction disorders, and (3) anemia from blood loss enables a clear understanding of the pathophysiology of this disease.

Clinical Presentation

The presentation of anemia can be variable, depending on the acuteness of onset and the ability of the cardiopulmonary system to compensate. If the patient is healthy and the onset of anemia is gradual, there are few signs or symptoms until the hemoglobin value falls below 7.5 g/dL.⁶ Patients may initially experience fatigue, malaise, headache, dyspnea, irritability, and a mild decrease in exercise tolerance. Further declines in hemoglobin concentration may be associated with a markedly reduced exercise capacity, resting tachycardia, and dyspnea requiring supplemental oxygen. Other nonspecific findings that can accompany long-term, moderate to severe anemia include wide pulse pressure, midsystolic or pansystolic murmur, confusion, lethargy, brittle nails, glossitis, angular cheilitis, and spoon-shaped nails.⁴ Pallor of the mucous membranes, lips, conjunctivae, nail beds, and palmar creases is a common sign of anemia. When palmar creases are as pale as the surrounding skin, the patient usually has a hemoglobin value of less than 7 g/dL.⁶

Physical Examination

A head to toe physical examination is warranted in the evaluation of a patient with anemia. Overall appearance suggestive of decreased stamina and energy could suggest fatigue secondary to anemia, or anemia related to another chronic illness. A thorough cardiopulmonary examination including vital signs is essential. Increased heart or respiratory rate or the presence of a systolic murmur may be related to anemia. Special attention should be paid to characteristics of the integumentary system to evaluate for pallor, nail integrity, and signs of angular cheilitis. Also, symptoms of increased bruising may be a clue to a potential bleeding disorder contributing to blood loss and iron deficiency.

Diagnostics

Diagnostic evaluation of anemia initially should include a complete blood count (CBC) including platelet count, white cell differential, RBC morphology, reticulocyte count, and a peripheral blood smear. Evaluation of all blood cell lines is essential to confirm a sole anemia diagnosis, as opposed to a primary bone marrow disease such as aplastic anemia or an infiltrative process such as leukemia. Of the multiple indexes noted on a CBC report, the mean corpuscular volume (MCV) is the single most useful. Describing RBCs as microcytic, normocytic, or macrocytic based on the MCV determines what other testing is necessary to determine the cause of the anemia.

The reticulocyte count is the most easily accessible method of evaluating bone marrow production of RBCs (a direct bone marrow examination requires an invasive procedure). The reticulocyte count provides an assessment of whether the causative factor of anemia is related to either decreased production or increased loss. A normal reticulocyte count is 0.5% to 1.5% of the total RBCs. A normal absolute reticulocyte count (ARC) is 25,000 to 75,000/µL. Any value higher than 100,000/µL is considered a marrow that is responding normally to anemic conditions. Values below 75,000/µL are considered consistent with impaired (decreased) RBC production.⁴ However, if reticulocytosis is associated with anemia, hemolysis needs to be ruled out by observing for hyperbilirubinemia (marker of hemoglobin catabolism) and increased serum lactate dehydrogenase (LDH), which is indicative of direct cellular injury. Also, a low serum haptoglobin value is a sign of intravascular hemolysis because haptoglobin binds the free hemoglobin that is released into the circulation as erythrocytes rupture. These hemoglobin-haptoglobin complexes are removed from the circulation by the reticuloendothelial system. Hemolytic anemias are complex to evaluate and diagnose; if they are suspected, referral should be made to a hematologist. A low reticulocyte count with anemia points to impaired erythropoiesis indicating a reduction in RBC precursors or ineffective production. Ineffective production is reported as erythroid hyperplasia on the bone marrow biopsy and aspiration report. This means the RBCs are being produced but are not viable and usually do not leave the marrow. Box 237-1 identifies conditions associated with either reticulocytosis or a decreased reticulocyte count.

Evaluation of the body’s iron stores includes serum ferritin, serum iron, total iron-binding capacity (TIBC), and transferrin saturation percentage. The serum ferritin level reflects total body iron stores. It is the first laboratory value to become abnormal when iron stores are becoming depleted, even before IDA is reflected in RBC morphology. Ferritin concentrations less than 12 ng/mL indicate absence of iron stores. It is important to remember, however, that ferritin is an acute-phase reactant and may be elevated as a result of inflammation. Inflammation causes the release of tissue ferritins resulting from damage to the liver and other ferritin-rich tissues.⁷ Serum ferritin levels are low in IDA and normal or elevated in ACD. Serum ferritin is also elevated in conditions unrelated to anemia, such as iron overload (either transfusion dependent or hereditary hemochromatosis), inflammatory disorders, and alcoholism.

The serum iron concentration reflects the amount of iron bound to transferrin, a plasma carrier protein that regulates iron transport in the blood. Normal values for serum iron are 65 to 165 µg/dL.⁷ Transferrin is the transport protein for iron and is measured indirectly by the TIBC. The TIBC indicates the availability of binding sites on the protein for iron transport. Normal values for TIBC are 300 to 360 µg/dL.⁷

The percentage of transferrin saturation can be calculated from the TIBC and the serum iron values as follows:

Serum ironTIBC×100

Normal values for percentage of transferrin saturation are 20% to 50%.⁷

Physician consultation is recommended for hemoglobin values of less than 10 g/dL in patients with known coronary artery disease and for any patient with postural vital sign changes or active bleeding. Physician consultation is also recommended for sickle cell crises, suspected aplastic anemia, or hemolytic anemia.

Differential Diagnosis

Anemias are generally divided into three categories based on the size of the RBCs suggesting the underlying condition or disease. RBCs are normally uniform in size and shape, and deviations in their appearance can suggest a specific cause for the anemia. The degree of anisocytosis (variation in RBC size) is determined by looking at the RBC indexes on the CBC and at cell morphology on the peripheral smear. The most useful RBC index is the MCV. The MCV is a direct measurement averaging the RBC sizes in the sample. The RBC distribution width (RDW) is an indirect measurement that indicates the degree of homogeneity of the sample. For example, uniformly small RBCs will have a low MCV and a normal RDW, whereas a sample with mostly small RBCs but some normal RBCs can have a low MCV with an increased RDW, reflecting the heterogeneity of the sample. Based on the MCV, anemias are classified as microcytic (MCV <80 fL), normocytic (MCV 80 to 99 fL), or macrocytic (MCV >100 fL).⁴ Variations in RBC shape (poikilocytosis) provide important diagnostic clues and in fact are often pathognomonic of underlying disease. Box 237-2 classifies commonly seen hematologic disorders according to RBC morphology.

Pathophysiology

Iron is an essential nutrient present in all living cells. The human body contains about 3 to 4 g of iron, with more than 70% contained within hemoglobin. The remainder of the body’s iron is stored in the liver and marrow as ferritin and hemosiderin, and a small amount is bound to transferrin in the blood.³ The normal man has a total body iron content of about 4000 mg. Women of childbearing age have about 2000 mg of total body iron, a significantly lower amount because of menstrual blood loss and lower dietary intake. The average adult normally loses approximately 1 mg of iron each day through the natural process of desquamation of cells from the skin, GI tract, and urinary tract. The adult woman loses an additional 1 mg through normal menstruation.

The recommended daily allowance of iron is 15 mg/day in the diet of nonpregnant women and 30 mg/day for pregnant women. Dietary iron is absorbed in the duodenum of the small intestine. The amount of iron absorbed from the intestine is determined by several factors, including the iron content of the meal, the form of iron being ingested, the individual’s iron status, and the presence or absence of other substances that can enhance or inhibit iron absorption (Box 237-4).⁹

Mild to moderate iron-deficient states are not associated with any clinical symptoms. Patients with severe IDA exhibit the same signs and symptoms of any type of severe anemia. Patients may complain of fatigue, decreased exercise tolerance, weakness, palpitations, irritability, and headaches. Complaints that are specifically related to iron store depletion include paresthesias, sore tongue, brittle nails, spoon-shaped nails (koilonychia), and pica for starch, ice, or clay.⁵ In fact, a craving for ice (pagophagia) is a common symptom of women with IDA for unknown reasons.

Physical Examination

As the severity of the anemia increases, several physical changes may become evident. The patient may demonstrate a more forceful apical pulse, tachycardia with exertion, and a systolic flow murmur. Patients may also demonstrate pallor of the conjunctiva, mucous membranes, nail beds, and palmar creases. The characteristic spooning of the nails may also be present. In the older adult, signs of congestive heart failure may be present.

Diagnostics

IDA is commonly discovered incidentally during a routine CBC. Once IDA is diagnosed, the history may reveal factors that would cause iron deficiency, such as a recent hemorrhage, GI bleeding, menorrhagia, multiple pregnancies, or inadequate nutrition. Iron studies reveal a low serum iron level, decreased serum ferritin, increased TIBC, and decreased percentage of transferrin saturation (Box 237-5). Laboratory changes occur gradually as the iron stores are depleted. The earliest laboratory change is a fall in serum ferritin, reflecting depletion of iron stores. This change is followed by a decrease in serum iron and an increase in transferrin, producing a reduction in the percentage of transferrin saturation to less than 15% (this will drop below 10% as the severity progresses) and an associated increase in TIBC. The first change in the CBC is a drop in hemoglobin. Only with increasing severity and duration do the RBCs become microcytic and hypochromic.

ACD presents a more common diagnostic dilemma. With long-standing chronic inflammatory illnesses such as rheumatoid arthritis, the defective iron supply can result in severe microcytic hypochromic anemia. Iron studies, especially the serum ferritin level, usually differentiate among true IDA, ACD, and thalassemia (Table 237-1). Both IDA and ACD are associated with low serum iron levels. The ferritin level is normal or increased in ACD and decreased in IDA. The TIBC is normal or low in ACD and increased in IDA.

Microcytosis can occur in patients with inherited sideroblastic anemias; however, these anemias are rare and are related to X-linked genes. Acquired sideroblastic anemias (idiopathic, secondary to drug or toxin exposure, myeloproliferative or myelodysplastic disease) can be microcytic but generally are macrocytic. These conditions are caused by defects in heme synthesis leading to accumulation of iron within bone marrow erythroid precursors and resulting in abnormal erythroid maturation. This anemia is characterized by ringed sideroblasts (erythroblasts with one third or more of the nucleus surrounded by ferritin deposits).³ A bone marrow examination is necessary for diagnosis. The anemia tends to be severe (hemoglobin concentration of 6 g/dL) to moderate (hemoglobin concentration of 8 to 10 g/dL). Treatment of sideroblastic anemia consists of chronic transfusions and iron chelation therapy (to prevent or to treat the transfusion-dependent iron overload). Pyridoxine (vitamin B₆) therapy may sometimes partially correct the anemia in patients with hereditary sideroblastic anemia, leaving them with a milder anemia that does not require as many chronic transfusions.

If the anemia is severe, the patient has an iron malabsorption problem, or oral iron is not tolerated, replacement should be by parenteral (intramuscular or intravenous) administration of iron. Patients should be referred to a hematologist for intravenous administration of iron because it has traditionally been associated with adverse reactions. There are newer intravenous iron formulations (iron carboxymaltose and ferumoxytol) that appear to have a much safer profile. The novel structures of these preparations have been shown to reduce the risk of free iron reactions and result in lower immunogenicity. As a result, test doses are not necessary and much higher doses can be administered, thereby reducing the number of administrations necessary to replace iron stores.¹⁰

Life Span Considerations

Children require adequate iron intake to meet the increased demands of rapid growth. Nutritional iron deficits are especially common in children with excessive milk consumption at the expense of adequate intake of iron rich foods.

Teenage girls often become iron deficient as a result of menstrual blood loss, sometimes accompanied by poor diet in this age group.

Iron supplementation during pregnancy is almost always required. Pregnancy places a greater demand on iron stores, especially during the last two trimesters. The additional iron is needed to cover the needs of the developing fetus and placenta and to accommodate the increase in erythrocyte mass that normally occurs during the later stages of pregnancy. Many women enter pregnancy with inadequate iron reserves as a result of prepregnancy menstruation. Iron studies can be difficult to interpret in pregnancy because of the hemodilutional effects of the increase in blood volume during pregnancy, as well as the elevation of ferritin as an acute-phase reaction to the known inflammatory effects of pregnancy. Adequate maternal iron stores are essential to adequate brain development in the fetus.¹¹

Older adults with suspected IDA should be thoroughly evaluated for GI cancers, even when their stools are negative for occult blood. Next to chronic disease, iron deficiency is the most common cause of a microcytic anemia in older adults.

Complications

Untreated IDA is especially worrisome during pregnancy. IDA may be associated with preterm delivery, low birth weight, and learning deficits. Untreated iron deficiency in all age groups can lead to severe anemia and may be associated with fatigue, falls, and cardiovascular compromise.

Indications for Referral or Hospitalization

Most patients with IDA are diagnosed and treated by their primary health care providers. Patients who are referred to a hematologist for any of the aforementioned reasons are generally referred back to the primary health care provider once the anemia has been corrected, or at least once an accurate diagnosis has been made and the patient is receiving stable iron replacement therapy.

Referral to a hematologist should be considered for the following reasons: nonadherence to or intolerance of oral iron replacement, persistent IDA necessitating parenteral iron therapy, and persistent microcytic anemia despite iron replacement and the exclusion of other conditions.

Other referrals may be required as evaluation for the cause of the iron deficiency progresses, such as referral to an internist or gastroenterologist to exclude GI blood loss or referral to an oncologist to treat any malignant neoplasms (either GI or gynecologic). Women of reproductive age may require referral to a gynecologist or a hematologist for evaluation of severe menorrhagia (the hematology referral may be helpful to rule out von Willebrand disease as a cause of the menorrhagia).

Healthy patients with IDA do not require hospitalization. Patients who are unable to adequately compensate for severe anemia may require hospitalization for cardiac or respiratory compromise that may occur.

Patient and Family Education

Patients should receive education about the use of iron supplements to ensure adequate treatment and an understanding of the prescribed regimen. Maximum absorption of iron occurs if it is ingested 30 minutes before meals. Substances that can enhance or inhibit iron absorption are listed in Box 237-4. Calcium can significantly inhibit iron absorption. Multivitamins with calcium or dairy products should be taken 1 to 2 hours after an iron supplement. Ascorbic acid may enhance absorption of iron; therefore, concurrent ingestion of foods rich in vitamin C, such as orange juice, should be encouraged.

Numerous iron supplementation preparations are on the market (Table 237-2), some with combinations of iron plus stool softeners, slow-release iron, or iron plus vitamin C. Patients who are intolerant of one preparation may find another that produces fewer or no side effects. The health care provider should therefore encourage patients to try various preparations before recommending parenteral iron.

Pathophysiology

The manifestations and severity of clinical symptoms depend on the number of chain deletions in the hemoglobin molecule. Normally, adult RBCs contain predominantly hemoglobin A₁ (96% to 97% of the cell’s hemoglobin) and only small amounts of hemoglobin A₂ (2.5%) and hemoglobin F (<1%).⁴ Thalassemia abnormalities produce changes in the normal amounts of adult hemoglobin. These quantitative changes are important in the diagnosis of thalassemia.

Inheritance of thalassemia occurs in a mendelian-recessive manner¹² (Fig. 237-1). The two main types of thalassemia are α (alpha) and β (beta), the two protein chains required to make normal hemoglobin. Four genes (two from each parent on chromosome 16) are involved in making α-globin. If one gene is affected, the person is called a silent carrier and usually has no symptoms. If two genes are affected, individuals are considered carriers and have mild anemia (α-thalassemia trait or α-thalassemia minor). People with hemoglobin H (α-thalassemia intermedia) disease have three genes affected and are moderately to severely anemic.¹³ When all four genes are affected, the condition is called α-thalassemia major (hemoglobin hydrops fetalis), and most affected fetuses are born prematurely and stillborn or die shortly after birth.¹³ The patients who survive will require lifelong transfusions and extensive medical care.