CHAPTER 29

ANEMIA

Dolores J. Bacon, M.D.

  Table of Contents

            Anemia is defined as a reduction in circulating red blood cells. Erythrocyte mass is usually tightly regulated, with 200 billion RBCs turning over each day in the average 70-kg adult. Anemia is the result of an imbalance between the production of erythrocytes and physiologic demand caused by blood loss, increased destruction, decreased production or sequestration of red blood cells. In general, anemia is defined as a hemoglobin concentration below 13 g/dl (or a hematocrit below 42 percent) for men and a hemoglobin below 12 g/dl (or hematocrit below 37 percent) for women. These should not be considered absolute values, because the “normal” range of hemoglobin follows the usual bell-shaped curve, implying that 2.5 percent of healthy individuals will have blood counts in the “anemic” range.

            When evaluating anemia, there are certain facts to remember. The first is that there are several states in which a reproducible fall in hematocrit is considered normal (in pregnancy, for example).[i]^,[ii] Secondly, hemoglobin levels are slightly lower in African American populations (0.5 to 1.0 gm/dl lower) than in Caucasian populations.[iii]^,[iv] Thirdly, age does not affect erythropoiesis in adults. Anemia in an elderly person, therefore, should never be attributed to aging. Lastly, there is no correlation between the degree of anemia or extent of symptoms and the severity of the underlying cause. For these reasons, the etiology of anemia should be pursued in all patients.

Evaluation

            A systematic approach will make the work-up easier and help to establish the diagnosis efficiently. The following steps should be routinely included:

1.      Verify that an anemia does indeed exist by repeating the hemoglobin and hematocrit.

2.      Are there any factors that influence Hb level (volume status, pregnancy, altitude)?

3.      Obtain a detailed history (see Table 1).

4.      Perform a careful physical exam (see Table 2).[v]^,[vi]

TABLE 1: Anemia - important aspects of the history

TABLE 2: Anemia - important aspects of the physical exam

Laboratory Evaluation

          The goal should be to order those tests most likely to give useful information. Having discovered an anemia (usually on a CBC), we already have important information at hand: the peripheral smear and mean corpuscular volume (MCV). Actually looking at the peripheral smear can be invaluable, as a normal MCV may be misleading (in a mixed population of macrocytes and microcytes, for example). Similarly, a high RDW implies a mix of erythrocytes of different sizes. While color and shape can be critically important, most anemias are classified by MCV: microcytic, normocytic or macrocytic. This is often described as the “morphologic approach” to anemias. Another way to think about the evaluation of anemia is the “kinetic approach” – determining whether the anemia is caused by decreased RBC production, increased RBC destruction, or RBC loss.

Microcytic Anemia

A low MCV (less than 80 fL) implies impaired globulin synthesis, defective or decreased hemoglobin synthesis or defective porphyrin synthesis. The most common disorders causing microcytic anemia in general practice are iron deficiency anemia, the anemia of chronic disease, thallasemia minor and sideroblastic anemia. Evaluation should include iron studies (serum iron, TIBC and ferritin levels). You should then calculate the transferrin saturation (Fe/TIBC = percent saturation). A saturation of less than 16 percent indicates that there is insufficient iron for erythropoesis, as seen in iron deficiency anemia. If the ferritin is less than 35, iron deficiency is present. If the saturation is above 50 percent, think AOCD: if it is 16 - 50 percent, think thalassemia or sideroblastic anemia.

IRON DEFICIENCY ANEMIA:

            Iron deficiency anemia is the most common cause of microcytic anemia. It is most often caused by blood loss, but can be caused by impaired iron absorption or inadequate dietary iron (both of which are rare). Iron absorption occurs in the duodenum and proximal jejunem and is related to total dietary iron intake, as well as to its bioavailability. A small amount of iron is lost daily via sweat, skin desquamation and GI tract shedding, and a small amount is absorbed from the diet. The remainder is “recycled” from body iron stores. Iron absorption is impaired by iron chelators, such as phosphates, teas, some cereals and some drugs. Citrates and vitamin C, in contrast, promote iron absorption by forming soluble complexes. Increased losses of 20 mg/month can be seen in menstruating women and 500 mg can be lost at a normal delivery.

            The first indication of depleted body iron stores is a decreased ferritin level (less than 35), which is very specific for iron deficiency. A normal ferritin level does not rule out iron deficiency, however, as it is an acute phase reactant and often rises in the presence of chronic inflammation, liver dysfunction, malignancy or infection. In the presence of these conditions, a ferritin level that is normal but less than 50 is highly suggestive of iron deficiency. Serum transferrin receptor levels are not affected by inflammation or age, and may be differentiate iron deficiency anemia and anemia of chronic disease more accurately – the use of this marker is currently investigational.[vii]

            The next changes that occur are a decrease in serum iron and increase in TIBC. Microcytosis occurs after several months of decreased total body iron stores. The definitive test for iron deficiency is the demonstration of absence of iron on a Prussian blue stain of bone marrow aspirate, but this is usually unnecessary to make the diagnosis.

TABLE 3: Evaluation of iron deficiency anemia

ANEMIA OF CHRONIC DISEASE:

            Anemia of chronic disease (AOCD) is generally a diagnosis of exclusion.[ix]^,[x] The pathogenesis is thought to involve a decrease in the red blood cell life span (which is normally 120 days) with a concomitant inability of the marrow to respond by increasing erythrocyte production. Humoral factors such as tumor necrosis factor, interleukin-1 and prostaglandins, which are released in infections and inflammatory disorders, contribute to the development of anemia by suppressing erythropoiesis. Patients with AOCD have an inappropriately low erythropoieitin level. Management is best directed towards the identification and treatment of the underlying disease, but transfusions may be given if the anemia is severe.

TABLE 4: Evaluation of anemia of chronic disease

THALASSEMIA:

            The thalassemias are hereditary hemoglobinopathies involving defective synthesis of one or more globin chains and resulting in hypochromic, microcytic anemia. Adult thalassemia will be the heterozygous forms (since the homozygous result in severe disease and early death). The silent carrier state of alpha thalassemia is the result of a single gene deletion; carriers have no hematologic abnormalities. In the presence of two gene deletions (either homozygous alpha-thal 2 or heterozygous alpha-thal 1) patients will have a microcytic anemia. Hemoglobin electrophoresis is normal except for decreased amount of HbA2. The beta-thalassemias can be found alone, or in compound heterozygous presentations such as sickle-beta-thalassemia. Hb electrophoresis will show increased HbA2 (and possibly HbH or F).

TABLE 5: Evaluation of thalassemia

SIDEROBLASTIC ANEMIA:

            The sideroblastic anemias are either hereditary (rare) or acquired (associated with drugs, such as INH, toxins, inflammatory or neoplastic disease). A characteristic finding is ringed sideroblasts (iron laden mitochondria surrounding the nucleus of erythroid precursors) seen in the bone marrow. The most common cause of acquired sideroblastic anemia is ethanol abuse.

TABLE 5: Evaluation of sideroblastic anemia

Normocytic Anemia

            The differential diagnosis of normocytic anemia is extensive. The first lab test to order is a reticulocyte count. If elevated, consider a drug-related, autoimmune or hereditary hemolysis. Associated lab abnormalities include elevated serum LDH and unconjugated bilirubin and a low serum haptoglobin. A Coombs test should be requested, as it is a marker for autoimmune hemolytic anemia. Examination of the peripheral smear will provide clues for the next step in the work-up. For example, if sickle cells are noted, Hg electrophoresis is indicated. Nucleated RBCs should prompt both Hg electrophoresis and bone marrow biopsy. Red cell fragments suggest an evaluation for DIC.

            When the reticulocyte count is not elevated, consider conditions that result in reduced or defective RBC productions. Some examples include chronic renal failure, adrenocortical insufficiency, hypopituitarism, hypothyroidism, androgen deficiency, early iron deficiency, myelotoxic drugs, HIV, metastatic infiltration and 1° marrow failure.

TABLE 6: Evaluation of normocytic anemia

Macrocytic Anemia

            Macrocytic anemias are classified as megaloblastic or non-megaloblastic. The first step in the evaluation of a macrocytic anemia is to examine the smear for hypersegmented neutrophils. The majority of megaloblastic anemias are due to cobalamin deficiency, or to ethanol-related folate deficiency. Although dietary folate can be deficient in the elderly (or alcoholic) population, vitamin B12 deficiency is more often due to impaired absorption than to an inadequate diet. Pernicious anemia results from lack of intrinsic factor; it is most often seen in the elderly. Physical exam can reveal glossitis and decreased vibratory and position sense. Approximately 50 percent of patients with pernicious anemia have antibodies to intrinsic factor, and in advanced cases, pancytopenia can be seen. Sprue is another common cause of cobalamin deficiency. Sixty percent of patients with macrocytosis are not anemic;[xi] these patients should still be evaluated as the first indication of cobalamin or folate deficiency is often macrocytosis.

TABLE 7: Causes of macrocytic anemia

            The nonmegaloblastic anemias can be grouped into those disorders associated with an elevated reticulocyte count (such as hemolytic anemia or hemorrhage), and those associated with a normal or decreased reticulocyte count (such as EtOH abuse, chronic liver disease, hypothyroidism, medications and myelodysplasias). When ordering lab tests to evaluate a macrocytic anemia, remember that in the presence of severe anemia, there is a compensatory marrow response, resulting in increased RBC production and premature reticulocyte release. To evaluate the appropriateness of the reticulocyte count, a correction for the degree of anemia must be calculated: corrected reticuloctye count = reticulocyte count x (measured Hct/45).

TABLE 8: Evaluation for macrocytic anemia