Larry Waterbury
General Considerations
Anemia is a reduction of the proportion of red blood cells (RBCs) or of hemoglobin in the blood. It is a condition, like hypoxia or jaundice, that always reflects a primary underlying disease. Although sometimes symptoms (e.g., shortness of breath on exertion) or signs (e.g., pallor) are associated with anemia, the diagnosis of the condition depends essentially on one or more laboratory measurements, such as the hematocrit value (Hct) or the hemoglobin concentration (Hb). In general, anemia in a man is defined as an Hct <42% or Hb <14 g/100 mL and in a woman as an Hct <37% or Hb <12 g/100 mL. When anemia is diagnosed, other measurements (see Approach to Evaluation of Anemia) are important in establishing the cause of the process and selecting appropriate therapy.
Most routine complete blood counts (CBCs) obtained in clinical practice in the United States are determined by automated counting methods (Table 55.1). The CBC usually reports Hb, Hct, RBC count, white blood cell (WBC) count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). One commonly used automated system (Coulter) measures Hb, RBC, and MCV and from these variables calculates the Hct, MCH, and MCHC. Using automated counters, the indices MCH, MCHC, and especially MCV are precise, accurate measurements that can be used in approaching the diagnostic workup of anemia. The calculated Hct is slightly lower than that obtained by centrifugation (packed cells trap plasma, distorting the ratio of red cells to plasma). The red cell distribution width (RDW) calculated by most automated systems is a measure of variation in size. It often is increased in many anemias, such as moderate to severe iron deficiency, megaloblastic anemias, many hemolytic anemias, and anemias associated with reticulocytosis.
Approach to Evaluation of Anemia
The routine database that should be obtained for every anemic patient includes Hct, Hb, MCV, MCHC, and reticulocyte count (Table 55.2). A smear of the peripheral blood
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should be examined. Based on all of these data and a complete history and physical examination, the clinician can progress a long way toward an etiologic diagnosis of the anemia. Three questions should be asked:
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TABLE 55.1 Representative Normal Values (Coulter S) |
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TABLE 55.2 Routine Database for Anemic Patients |
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TABLE 55.3 Reticulocyte Index |
In summary, the initial database should enable the physician to classify the anemia based on MCV, categorize the basic mechanism of the anemia, and consider possible causes based on the patient's problem list. This initial assessment should then suggest appropriate further diagnostic workup.
Anemia With a Low Mean Corpuscular Volume
Table 55.5 lists the anemias commonly associated with a low MCV. For the most part, the diagnosis rests between iron-deficiency anemia and thalassemia. Occasionally the anemia of chronic inflammation or, even more rarely, of sideroblastic anemia is microcytic; more often, they are normocytic or, in the case of sideroblastic anemia, macrocytic.
Iron-Deficiency Anemia
Although dietary iron deficiency does occur in the infant and during the rapid growth phase of adolescence, in the
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United States iron deficiency usually occurs only as a result of bleeding. Iron deficiency from menstruation and pregnancy is extremely common in women; however, iron deficiency in a man or in a postmenopausal woman should be considered to be caused by gastrointestinal bleeding until proven otherwise.
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TABLE 55.4 Anemias Associated with Various Clinical Settings |
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Diagnosis
The history and physical examination may yield information that suggests the presence of iron deficiency (1). Such information includes a history of multiple pregnancies in a woman; strange dietary habits such as the eating of ice, starch, or clay (pica); any history of gastrointestinal bleeding; and physical findings of a sore tongue, brittle and ridged fingernails, spoon nails, or cheilosis. The physical findings are seen only in patients with long-standing, severe iron deficiency.
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TABLE 55.5 Causes of Anemia with Low Mean Corpuscular Volume |
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Most of the body's iron is incorporated in hemoglobin, but approximately one third of the iron is stored in reticuloendothelial sites, primarily in the spleen, liver, and bone marrow. In patients with slow continued bleeding, the reticuloendothelial iron stores supply iron to the bone marrow until the stores are depleted. At this point, iron-deficiency anemia begins to develop. In iron deficiency, cell size (MCV) correlates with the degree of anemia, so very mild iron-deficiency anemia may be associated with normal-size cells (see Mild “Early” Iron Deficiency) (2). MCV progressively decreases as the anemia becomes more severe, but MCHC usually remains normal until the Hct falls to <30%. As the anemia becomes more marked, the
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red cells also become progressively more distorted (poikilocytosis). Table 55.6 lists the relationship among Hct, MCV, and the degree of red cell distortion (poikilocytosis) seen in iron-deficiency anemia of varying degrees of severity.
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TABLE 55.6 Representative Database at Various Stages in the Slow Development of Severe Iron-Deficiency Anemiaa |
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Often the diagnosis of iron deficiency is obvious after the initial history, physical examination, and standard laboratory evaluation. If not, a number of other tests may be useful. One of the most useful is a baseline MCV measurement, because iron deficiency is an acquired microcytic anemia and in thalassemia microcytosis is lifelong. The reticulocyte index is inappropriately low for the degree of anemia. Theserum iron (SI) concentration is low, but it also usually is low in patients with acute or chronic inflammation or malignancy. Furthermore, an acute infectious process such as pneumococcal pneumonia causes an immediate drop in the SI concentration, even though the patient is not iron deficient. Classically, the total iron-binding capacity (TIBC) is elevated. TIBC is a measure of serum transferrin, the iron transport protein that supplies bone marrow RBC precursors with iron. However, many iron-deficient patients have a normal TIBC, and TIBC may be low in cases of chronic inflammation or malignancy regardless of whether iron deficiency is present. In iron deficiency, cell receptors (marrow red cells) for transferrin increase and result in an increase in circulating transferrin receptor levels, which can be measured. This test can be helpful in distinguishing iron deficiency from the anemia of chronic disease (3), but the sensitivity and specificity are relatively low (4) nor is the test universally available. In fact, none of these tests is completely reliable in the diagnosis of iron deficiency, especially in patients with comorbidities.
Measurement of serum ferritin is the most useful noninvasive test in the assessment of body iron stores (5). Ferritin is a water-soluble complex of iron and the binding protein apoferritin. The serum ferritin concentration reflects the status of the reticuloendothelial stores and, in general, is a more specific test than SI and TIBC in the diagnosis of iron deficiency. A low serum ferritin concentration almost always reflects iron deficiency. A very high serum ferritin concentration usually signifies iron overload, as in the patient who has received multiple transfusions. However, in many situations (e.g., inflammatory disease, chronic renal failure), the serum ferritin measurement may be spuriously normal or even elevated in the presence of iron-deficiency anemia (Table 55.7). In these situations, it may be difficult to make a definitive diagnosis of iron deficiency without a bone marrow iron stain. Response to a therapeutic trial of iron may allow a presumptive diagnosis of iron deficiency. In general, it is inappropriate to subject people to an expensive and uncomfortable evaluation of the gastrointestinal tract without persuasive proof of iron deficiency or evidence of gastrointestinal bleeding. On rare occasions, proof of iron deficiency may require a bone marrow iron stain. The bone marrow iron stain is the most definitive way to prove a diagnosis of iron deficiency because iron stores are depleted when iron-deficiency anemia is present and are normal or elevated in patients with microcytic anemia from other causes.
Treatment
After institution of oral iron therapy, the reticulocyte response is maximal at approximately 7 to 10 days. The Hct begins to rise after approximately 1 week and, in the uncomplicated case, reaches a normal level in a few weeks.
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However, many months of therapy are required for repletion of iron stores (the status of which can be evaluated by repeat measurement of serum ferritin after iron therapy is concluded). Iron absorption is variable and unpredictable. Only a fraction of ingested iron is absorbed, even under optimal conditions. In the menstruating woman with iron-deficiency anemia, treatment for 1 year or longer may be necessary. Iron deficiency is common in menstruating women, especially in those with heavy menstrual periods and a history of multiple pregnancies. Some women may require perpetual iron therapy to maintain a normal Hct level. Standard treatment with oral iron consists of one tablet of iron (e.g., ferrous sulfate 300 mg, which contains 60 mg elemental iron) taken three times daily on an empty stomach (1 hour before meals), separate from H2 blockers, antacids, and proton pump inhibitors. If patients experience difficulty taking the noontime dose, it reasonably can be omitted. Numerous preparations of iron other than ferrous sulfate are available, but recommendations for their use usually are not justified unless a reduction in the dosage of elemental iron is required (see Side Effects). Generally, time-release capsules and enteric-coated preparations are to be avoided. They are costly, and absorption is variable. Preparations containing iron, including ferrous sulfate, can be obtained without prescription.
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TABLE 55.7 Inappropriately Normal or Elevated Serum Ferritin Levels |
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Side Effects
Approximately 15% of patients have gastrointestinal side effects from oral iron, most commonly constipation, but nausea, abdominal cramping, and diarrhea also occur. If these side effects develop, the practitioner may elect to administer iron only once per day or may instruct the patient to take iron with meals instead of on an empty stomach (but not with tea or antacids). Taking iron with food decreases iron absorption by approximately 50%, but absorption still is sufficient to replenish the body's iron if treatment is continued long enough. If symptoms continue after these alterations in dosage and schedule, then decreasing the individual dosage of oral iron may be helpful. If the dosage is decreased to <40 mg elemental iron, symptoms often abate. This dosage decrease can be accomplished by using pediatric liquid preparations, which usually are well tolerated.
If these adjustments in the dosage and schedule of oral iron administration are made, parenteral iron is rarely indicated. However, parenteral therapy is indicated in patients with small or large bowel inflammation, rapid gastrointestinal transit, or malabsorption, or if the patient has severe iron deficiency and noncompliance has been repetitively proven. Iron dextran has been the most commonly used form of parenteral iron, but ferric gluconate in sucrose appears to be a safer preparation (6). It now is used preferentially in patients undergoing renal dialysis and may be prescribed to other patients as well. Parenteral iron usually is given in small doses intramuscularly or intravenously. If the intravenous route is chosen, the infusion must be given slowly. Guidelines for the dosage of parenteral iron are provided in the Physicians’ Desk Reference but can be calculated grossly from the patient's age and Hb value (Table 55.8). A test dose is administered 1 hour before the first therapeutic dose to ensure that the patient is not allergic to the preparation. Injections can be given daily until the calculated required dosage has been administered. Large doses of intravenous iron, appropriately diluted and given over several hours, are not approved by the U.S. Food and Drug Administration (FDA) but are generally safe when supervised by experienced clinicians. Side effects from parenteral iron include pain and rash at the injection site, arthralgias, staining of the skin, fever, and rare anaphylactoid reactions.
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TABLE 55.8 Representative Total Body Iron Deficits at Various Body Weights and Hemoglobin Levels |
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Thalassemia
In the normal adult, three types of hemoglobins are present in mature red cells: the major component A and two minor components A2 and F (fetal). Each hemoglobin molecule consists of four heme groups and four globin chains. The globin chains in each molecule are of two different types. All three hemoglobins have two α-globin chains but differ in their second set of globin chains (β, γ, or δ) (Table 55.9).
Thalassemia is an inherited defect in globin chain production. Anemia is caused by a combination of decreased hemoglobin production and, usually, mild hemolysis.
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β-Thalassemia is seen in the United States primarily in African American patients, patients from Southeast Asia, and patients of Mediterranean (Greek or Italian) origin. The genetics of α-thalassemia are complicated. The disorder appears to have a wider racial distribution than does β-thalassemia, but it is especially common in African Americans (7). Most patients are heterozygous and clinically asymptomatic, but they may have microcytosis. The diagnosis is important because the entity often is confused with iron-deficiency anemia, resulting in lifelong repetitive workups for gastrointestinal bleeding and inappropriate treatment with iron. Except possibly for menstruating women, microcytosis in African American patients is more likely to be caused by α-thalassemia than by iron deficiency.
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TABLE 55.9 Globin Chain Composition of Normal Adult Hemoglobins |
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TABLE 55.10 Heterozygous Thalassemia: Typical Database |
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Diagnosis
Table 55.10 lists the typical database for patients with heterozygous α-thalassemia or β-thalassemia. The combination of low MCV and only very mild anemia should alert the practitioner to the diagnosis because in iron deficiency the degree of microcytosis parallels the severity of the anemia (Table 55.6).
In the forms of β-thalassemia most commonly seen in the United States, production of β chains is decreased, with a compensatory increase in production of δ chains, resulting in decreased production of hemoglobin A and increased production of hemoglobin A2. This increase can be assessed by electrophoresis of the hemoglobin and is a definitive diagnostic test for β-thalassemia. Increases in hemoglobin F levels are seen less commonly in patients with β-thalassemia in the United States.
The α-thalassemias are more difficult to diagnose because decreased production of α chains affects the relative concentrations of all of the normal adult hemoglobins. A definitive diagnosis of one of the α-thalassemia syndromes may be difficult and may require family studies or techniques available primarily in research laboratories. However, the diagnosis of presumptive α-thalassemia in the setting of an appropriate database (hematologic values consistent with the diagnosis in the absence of iron deficiency and of β-thalassemia) is reasonable even in the absence of laboratory confirmation.
Patient Education
It is important to explain to patients with heterozygous thalassemia that the clinical features of the condition mimic those of iron deficiency. The patient should be put on guard against repetitive diagnostic workups for iron deficiency. The clinician should emphasize the benign nature of the illness and that the anemia, being mild, usually does not cause any symptoms. The patient should be cautioned against taking oral iron because thalassemic patients have increased iron stores. Genetic counseling is important. A couple, both heterozygous for β-thalassemia, has a 25% chance of having a child with homozygous β-thalassemia. Furthermore, the genes for thalassemia and those for hemoglobin S and C are alleles. Hemoglobin S–β-thalassemia is a clinically significant disease.
Miscellaneous
The anemia of chronic disease and the anemia of malignancy may be associated with a low MCV, although MCV usually is normal (seeAnemias with Normal Mean Corpuscular Volume and an Inappropriately Low Reticulocyte Index). Sideroblastic anemias (characterized by increased iron stores and ringed sideroblasts in the bone marrow) occasionally are microcytic, and some hemoglobinopathies are associated with a low MCV (hemoglobin E). The former conditions are best treated in consultation with a hematologist. The latter condition is seen primarily in Southeast Asians. Aluminum toxicity, now seen infrequently, sometimes causes a further reduction in red cell mass, with microcytosis (8).
Anemia With a High Mean Corpuscular Volume
An MCV >100 fL is abnormal, and an attempt should be made to explain the abnormality. Table 55.11 lists conditions associated with an increased MCV (9). For the most part, the diseases associated with an elevated MCV are liver disease, the megaloblastic anemias (including drug-induced megaloblastosis), and the refractory anemias with hypercellular bone marrows (myelodysplastic syndromes). Occasionally an elevated MCV measured by the automatic counter is spurious, caused by red cell antibodies (cold agglutinins). Because young RBCs are large, patients with a marked reticulocytosis may have an increased MCV.
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TABLE 55.11 Differential Diagnosis of Mean Corpuscular Volume >100 fL |
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Liver Disease
Chronic hepatocellular and obstructive liver disease results in cholesterol loading in the lipid portion of the red cell membrane so that cell size increases. MCV often is elevated but usually is not >115 fL (Table 55.12). On smears, cells appear to be round and centrally targeted, without significant variation in shape. This morphologic abnormality is not a cause of anemia. However, patients with liver disease often have other reasons for their anemia (bleeding, hemolysis, folic acid deficiency). The severe alcoholic often has an increased MCV even in the absence of overt liver disease or marked megaloblastosis (10). Presumably the elevated MCV results from periodic episodes of alcoholic liver disease, folic acid deficiency, or both. Because of poor diet, the alcoholic often becomes depleted of folic acid. In addition, alcohol interferes with folic acid metabolism.
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TABLE 55.12 Laboratory Features in Three Conditions Associated with Elevated Mean Corpuscular Volume |
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Megaloblastic Anemia
A megaloblast is a larger than normal hematopoietic precursor with a nucleus that contains characteristic granular chromatin, the result of abnormal deoxyribonucleic acid (DNA) synthesis (11,12). Table 55.13 lists the various etiologies of megaloblastic anemia related to deficiency of vitamin B12 (cobalamin) or folic acid (essential cofactors in DNA synthesis). The body's stores of B12 are such that a diet without this vitamin (one in which animal protein is completely excluded) would not result in megaloblastosis due to B12 deficiency for several years; therefore, dietary B12 deficiency is extremely rare. By far the most common cause of B12 deficiency is pernicious anemia, an acquired autoimmune defect of the gastric mucosa resulting in deficient formation of intrinsic factor, which binds ingested B12 and allows its absorption in the terminal ileum. Patients with pernicious anemia usually are elderly and often complain of sore mouth, indigestion, and constipation or diarrhea. Neurologic problems, including peripheral neuropathy, dorsal column dysfunction (loss of vibratory and position sense in the lower extremities), and changes in affect, are common. If the deficiency is not corrected, lateral column dysfunction (weakness and spasticity) occurs. The anemia develops so slowly that patients often have very low Hcts and yet remarkably good cardiovascular compensation for their anemia. Such patients usually have an expanded total blood volume and are prone to develop heart failure if given transfusions. B12 deficiency from other causes (Table 55.13) is less common. Patients who have undergone total gastrectomy or ileal resection
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or who have ileal disease (Crohn disease, tropical sprue) are likely to develop B12 deficiency and should receive prophylactic vitamin B12. B12 deficiency after partial gastrectomy is less common. Evidence indicates that B12 malabsorption may occur and lead to neuropsychiatric sequelae secondary to vitamin B12 deficiency despite normal hematologic values and normal Schilling tests (discussed later in this chapter). In such cases, vitamin B12 levels usually are low, although often not as low as in pernicious anemia. Diagnosis may require more sensitive (and more expensive) tests of B12 metabolism, such as measurement of serum or urine methylmalonic acid and serum homocysteine (13). The mechanism of B12 deficiency in such patients is unclear, although it may be caused, at least in some patients, by an inability to absorb food-bound B12 even though they secrete normal amounts of intrinsic factor (14). If this problem is suspected, the patient should be referred to a hematologist or neurologist for further evaluation. A therapeutic trial of vitamin B12 is often recommended.
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TABLE 55.13 Causes of Megaloblastosis Due to Vitamin B12 or Folic Acid Deficiency |
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In contrast to vitamin B12, the body's stores of folic acid are depleted rapidly when patients eat a diet deficient in folate. The main sources of folate in the diet are leafy vegetables, fruits, nuts, and liver. Therefore, the cause of folic acid deficiency most often is dietary. For example, pregnant women have an increased need for folate and without prenatal supplementation may develop folate deficiency, as may patients whose dietary intake is severely restricted because of chronic disease or multiple surgical procedures. Intestinal malabsorption for any reason is a common cause of folate deficiency. Finally, a number of drugs may be associated with folate deficiency: phenytoin (Dilantin) interferes with folate absorption, alcohol interferes with folate utilization, and methotrexate and trimethoprim–sulfamethoxazole (Bactrim, Septra) interfere with folate metabolism. Some chemotherapeutic agents (e.g., hydroxyurea, cytosine arabinoside, methotrexate, azathioprine) that are used in the treatment of cancer or for immunosuppression induction in patients with a variety of disorders cause megaloblastosis by inhibiting DNA synthesis.
Diagnosis
The morphology of the peripheral blood and bone marrow is the same in patients with folic acid deficiency and in those with vitamin B12deficiency (12). With severe megaloblastic anemia, MCV often is significantly increased. MCV >120 fL almost always is caused by a megaloblastic anemia. The red cells in the peripheral blood are characterized by marked variation in size and shape. The common cell is a macro-ovalocyte (large egg-shaped cell). Howell–Jolly bodies (nuclear fragments), Pappenheimer bodies (iron granules), and nucleated RBCs also may be seen. The nuclei of the neutrophils often are hypersegmented, and commonly neutropenia and thrombocytopenia are present. The bone marrow typically is markedly cellular, revealing characteristic megaloblastic changes of all cell lines. The bone marrow iron stain usually reveals increased numbers of iron-containing nucleated RBCs (sideroblasts).
Folic Acid and Vitamin B12 Assay
Classically, in vitamin B12 deficiency the serum B12 level is quite low (<100 pg/mL) and the serum folate level is high. Spuriously normal B12 levels occasionally are seen in B12 deficiency (see earlier discussion), and spuriously low levels may be seen without B12 deficiency in some patients with folic acid deficiency (Table 55.14). The serum folate assay has little clinical usefulness in the workup of megaloblastic anemia secondary to folic acid deficiency. The red cell folate concentration does reflect chronic folate deficiency, although it may be falsely low in some patients with vitamin B12 deficiency (Table 55.14).
Schilling Test
The Schilling test is a measure of B12 absorption. It requires the measurement of total radioactivity excreted during a 24-hour period after ingestion of radioactive vitamin B12. This test is useful primarily in cases where the data are confusing and for patients already treated with vitamin B12 in whom the serum levels are no longer helpful. The Schilling test requires a cooperative patient who can collect a 24-hour urine sample. The test includes the
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following steps: after voiding, the patient takes 0.5 µCi of cobalt-labeled vitamin B12 (cyanocobalamin Co 60 or Co 57) by mouth. A 24-hour urine collection is initiated. At 2 hours, 1 mg B12 is given by injection (the flushing dose), and the percentage of radioactive B12 excreted in 24 hours is determined. Normally ≥7% of the dose is excreted in 24 hours. Incomplete collection may result in a spuriously low Schilling test and a false diagnosis of B12 malabsorption. In addition, in the presence of severe megaloblastic anemia, changes in the gastrointestinal mucosa may affect B12 absorption. For example, the Schilling test may be abnormal in patients with folic acid deficiency, because of the effect of folate deficiency on the intestinal mucosa, until the megaloblastic process has been treated for 1 or 2 weeks (Table 55.15).
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TABLE 55.14 Vitamin B12 and Folate Concentrations |
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Table 55.16 outlines a stepwise approach to the use of laboratory tests in differentiating between folic acid and vitamin B12 deficiency in a patient with megaloblastic anemia.
After a diagnosis of vitamin B12 deficiency is established and treatment is initiated (see later discussion), periodic determination of serum vitamin B12 is not required.
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TABLE 55.15 Causes, Other than Pernicious Anemia, of a Positive Schilling Test |
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TABLE 55.16 Differentiating between Folate and B12 Megaloblastosis |
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Other Laboratory Features
Megaloblastic anemias essentially are hemolytic in that there is marked destruction of abnormally formed cells within the marrow (ineffective erythropoiesis), which often results in indirect hyperbilirubinemia and an elevated serum lactate dehydrogenase concentration. The SI concentration usually is elevated, and the reticulocyte index is inappropriately low.
Gastric achlorhydria is present in pernicious anemia. Antibodies to gastric mucosal cells and intrinsic factor are often present, as are other autoantibodies, especially antithyroid and antiadrenal antibodies. The most useful test in this regard is the assay of anti-intrinsic factor antibody in serum, which is reasonably specific for pernicious anemia and is present in approximately 70% of cases. Anti-intrinsic factor antibody assay may be helpful in the occasional patient with megaloblastic anemia of uncertain etiology. There is an increased prevalence of thyroid disease (hypothyroidism, hyperthyroidism, and euthyroid goiter) in patients with pernicious anemia.
Treatment
The traditional treatment for B12 deficiency is monthly intramuscular administration of 1,000 µg vitamin B12 for the rest of the patient's life. Many clinicians treat patients daily while they are in the hospital, particularly if they have neurologic signs; however, there is little evidence that this practice is more efficacious than simply starting maintenance
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monthly injections. There is evidence that B12 deficiency secondary to pernicious anemia can be treated successfully with oral vitamin B12, 2,000 µg per day (15). Although ingested vitamin B12 is primarily absorbed in the terminal ileum as a complex with intrinsic factor (see above), an alternate transport system may exist that allows the absorption of sufficient quantities of vitamin B12 when administered orally in high doses (11). Vitamin B12 tablets in doses up to 1,000 µg are available over the counter.
Folic acid 1 to 5 mg daily is adequate treatment for patients with folic acid deficiency. Treatment should be given at least until a normal Hct is reached and should be continued if the patient is not eating an adequate diet or if the underlying cause persists (e.g., malabsorption). Patients with a chronic hemolytic state, such as children with sickle cell anemia, patients on hemodialysis (folic acid is dialyzable), and pregnant women, should receive prophylactic treatment.
With appropriate treatment of megaloblastic anemia, rapid reticulocytosis occurs and reaches a peak at approximately 7 to 10 days. Hct begins to rise in approximately 1 week and, in uncomplicated cases, rises at a rate of four to five percentage points per week. The leukopenia and thrombocytopenia respond dramatically, and leukocyte and platelet counts may return to normal in 1 to 2 days. The responses of the neurologic complications of vitamin B12 deficiency are variable. Psychiatric symptoms usually abate dramatically. Dorsal column problems and peripheral neuropathies usually improve, but more slowly. Lateral spinal tract signs usually are refractory to treatment.
Myelodysplastic Syndromes
Myelodysplastic syndromes are acquired disorders of bone marrow stem cells that usually are seen in elderly patients and may mimic a megaloblastic anemia at presentation (16). However, the morphologic features of the bone marrow, and usually the peripheral smear, are different (Table 55.12). WBC and platelet morphology may be abnormal, serum vitamin B12 and folic acid levels are normal or high, and patients do not respond to folic acid or vitamin B12 therapy. In the bone marrow, ringed sideroblasts (red cell precursors containing granules of iron that form a ring around the nuclei) are common, as are “megaloblastoid changes.” Approximately 25% of patients develop acute nonlymphocytic leukemia, usually within 1 year but sometimes only after several years. Treatment frequently is supportive (transfusion, erythropoietin) (17), although a randomized controlled trial demonstrated the effectiveness of treatment with 5-azacytidine in selected patients (18). A number of other cytotoxic and immunosuppressive drugs have been tested, but none can yet be recommended for routine use. Patients who require more than supportive treatment should be referred to a hematologist or oncologist.
Anemias With Normal Mean Corpuscular Volume and Appropriate Reticulocyte Index (Hemolysis and Bleeding)
Anemias caused by bleeding and hemolysis are associated with an appropriate bone marrow response manifested by an appropriate reticulocyte index (Table 55.3). MCV usually is normal but may be slightly elevated if the reticulocyte count is very high. The diagnosis of hemolysis is suggested by an anemia with a reticulocyte index of at least 3% in the absence of overt bleeding. Bleeding is far more common than hemolysis, and bleeding in certain body sites (e.g., retroperitoneal bleeding in patients taking anticoagulants, bleeding into the site of a hip fracture) may be associated with a marked drop in Hct and a high reticulocyte count without external evidence of blood loss. Furthermore, correction of anemias that are caused by decreased bone marrow production may yield a database that mimics hemolysis, as in patients with an appropriate reticulocyte response after treatment with iron, folic acid, or vitamin B12 or after alcohol withdrawal.
Approach to Hemolysis
It is appropriate to attempt to prove the occurrence of hemolysis before obtaining diagnostic tests in a search for specific etiologies. The diagnostic approach to hemolysis varies depending on whether the hemolysis is primarily intravascular or extravascular.
Intravascular Hemolysis
Table 55.17 lists hemolytic mechanisms associated with intravascular destruction of RBCs. Almost all of the conditions require patient hospitalization, and, if possible, diagnostic testing and treatment planned in consultation with
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a hematologist. In intravascular hemolysis, red cell lysis occurs within the vascular space, resulting in hemoglobinemia. The plasma becomes visibly red or brown (methemoglobinemia) at a low hemoglobin concentration (approximately 30 mg/100 mL). Free hemoglobin initially binds to haptoglobin (a binding protein produced in the liver). Once haptoglobin is saturated, free hemoglobin passes through the glomerulus and hemoglobinuria occurs. Some of the hemoglobin in the renal tubules is absorbed by the renal tubular cells, which slough into the urine several days later and stain positively for iron (urine hemosiderin). Therefore, the latter test is helpful in documenting the presence of intravascular hemolysis several days after it has occurred. Table 55.18 suggests an appropriate database when hemolysis is suspected in the clinical states associated with intravascular hemolysis.
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TABLE 55.17 Clinical States Associated with Intravascular Hemolysis |
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TABLE 55.18 Appropriate Database when Intravascular Hemolysis Is Suspected |
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Extravascular Hemolysis
Most hemolysis occurs extravascularly within cells of the reticuloendothelial system. A diagnosis of extravascular hemolysis is more difficult to prove than that of intravascular hemolysis. There is no hemoglobinemia, hemoglobinuria, or hemosiderinuria. Haptoglobin is only partially saturated because there is only a slight leakage of free hemoglobin into the circulation. Indirect hyperbilirubinemia may be seen but is an insensitive sign of hemolysis. Fecal and urine urobilinogen levels increase but are difficult to quantitate. Other tests of hemolysis, such as red cell survival, are difficult, and the results are not known for several days. Often the clinician must be satisfied with only a presumptive diagnosis of extravascular hemolysis. Therefore, if extravascular hemolysis is suspected, it may be appropriate to obtain tests diagnostic of specific disease states based on a knowledge of the patient's other problems and on the baseline database (Table 55.19).
Information from the Peripheral Smear
In hemolytic states the peripheral smear often reveals only evidence of the response of the bone marrow to hemolysis (large polychromatophilic or finely stippled red cells). It is a common misconception that hemolysis always causes fragmented red cells on the smear; they are seen only in microangiopathic hemolytic anemias. However, the smear may give further clues about the specific cause of the hemolysis (as indicated below).
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TABLE 55.19 Most Common Causes of Extravascular Hemolysis |
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Spherocytes
Spherocytes are seen in small numbers in many hemolytic states. When present in large numbers, they suggest hereditary spherocytosis, autoimmune hemolysis, or one of the hemoglobin C hemoglobinopathies.
Elliptocytes
In large numbers, elliptocytes suggest a diagnosis of hereditary elliptocytosis.
Fragmented Cells (Schistocytes)
Sharply pointed, fragmented cells (helmet cells, spiculated cells, triangle cells) are seen in microangiopathic states (see later discussion).
Spiculated Cells
Spiculated cells are sometimes seen in patients with severe liver disease and hemolysis (usually in a terminal stage of liver disease). Spiculated cells are one type of schistocyte found in the blood of patients with microangiopathic hemolysis.
Bite Cells (Blister Cells)
Bite cells are sometimes seen in patients with oxidative hemolysis (e.g., G6PD deficiency). In bite cells, all of the hemoglobin appears to be pushed to one side of the cell.
Poikilocytosis and the Hemoglobinopathies
The peripheral smear often is diagnostic in patients with sickle cell disease or the various other sickle cell syndromes (see later discussion).
Hemolysis with a Positive Coombs Test
Once hemolysis is suspected, the diagnostic testing should be guided by the patient's problem list. Because of the relatively common occurrence of immune hemolysis and
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the important therapeutic implications of such a diagnosis, it is desirable to obtain a Coombs test at this stage of the workup (19,20).
Positive Direct Coombs Test
The direct Coombs test is done by mixing the patient's cells with Coombs antiserum containing antibody to immunoglobulin G (IgG) and to complement. If the test is positive, the clinician should first ascertain from the laboratory personnel that the positive result is attributable to antibody and/or complement on the red cell surface. If this is the case, it is important to determine whether the antibody is an alloantibody or an autoantibody.
Alloantibodies are antibodies induced by prior transfusion or, in a woman, by placental transfer of fetal red cells. The antibodies are directed against specific minor red cell antigens, and identification of these antibodies is important in case future transfusions are necessary. Ordinarily the antibody is present primarily in the patient's plasma and is identified by an antibody screen (indirect Coombs test). However, a direct Coombs test also would be positive because of the presence of alloantibodies if the patient had been recently transfused with cells that were still circulating and sensitized by the antibody.
In a patient with hemolysis but no history of a recent transfusion, a positive direct Coombs test usually implies the presence of an autoantibody. In this situation, the antibody may be present in the serum as well as on the surface of the red cells. Table 55.20 lists the differences between alloantibodies and autoantibodies. Autoantibodies are classified as either warm antibodies or cold antibodies. Warm antibodies usually are IgG and cannot be identified by direct agglutination of red cells; a Coombs test is required to detect them. Cold antibodies usually are IgM, cause direct agglutination of red cells in the cold, and result in a positive Coombs test because of fixation of complement to the red cell.
Hemolysis Caused by Warm Antibodies
Table 55.21 lists the conditions commonly associated with autoimmune hemolysis resulting from a warm antibody. Patients may develop such antibodies secondary to use of certain drugs or to any of a number of conditions, including infections (particularly viral), collagen vascular disease (systemic lupus erythematosus [SLE]), lymphoproliferative diseases, and other malignancies. The classic example of a drug that induces a positive Coombs test is α-methyldopa (Aldomet) (21).
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TABLE 55.20 Comparison of Alloantibody and Autoantibody |
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TABLE 55.21 Autoimmune Hemolysis Caused by a Warm Antibody: Differential Diagnosis |
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Autoimmune hemolysis is a relatively infrequent condition. Sometimes it precedes the development of SLE or lymphoma, but it may occur at any time during the course of the disease. Patients usually have anemia, which may be severe. On physical examination, the spleen is slightly enlarged in 50% of patients, and mild jaundice and fever are not uncommon. The peripheral smear shows marked polychromatophilia, spherocytosis, and often, but not always, an elevated reticulocyte index. Autoimmune hemolysis that is temporary, such as that caused by drug administration or viral infection, usually requires no treatment (although a drug, if implicated, should be discontinued). The process gradually remits over 2 to 3 weeks. Patients with chronic primary autoimmune hemolysis should be referred to a hematologist, who usually prescribes corticosteroids, which are generally effective if first given at a reasonably high dosage and slowly tapered as the anemia improves. Occasionally, splenectomy, cytotoxic drugs, or both are required for refractory cases. In patients with secondary chronic autoimmune hemolysis, treatment of the underlying disease is the most important therapy. Autoimmune hemolysis may present as a fulminant life-threatening anemia, sometimes associated with reticulocytopenia. In such cases, patients should be hospitalized immediately and transfused despite the incompatible cross-match.
Cold Agglutinin Hemolysis
The most common etiology of autoimmune hemolysis caused by a cold antibody is a viral illness or Mycoplasma pneumonia (22). Severe hemolysis is rare. Chronic idiopathic cold agglutinin hemolysis or cold agglutinin
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hemolysis secondary to a lymphoproliferative disease often is more refractory to treatment with steroids and splenectomy than is the case with warm antibody hemolysis. Transfusion therapy may be a problem in such cases because the antibody is a panagglutinin and reacts with all blood types; therefore, a compatible cross-match may be impossible to obtain. Ordinarily, the IgM antibody in cold agglutinin hemolysis is not significantly hemolytic, and transfusions with warmed washed red cells or plasmapheresis can be attempted when absolutely necessary (23).
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TABLE 55.22 Hemolysis with Fragmented Red Cells on Peripheral Smear: Differential Diagnosis |
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Hemolysis with Fragmented Red Cells on Peripheral Smear
Table 55.22 lists the conditions associated with hemolysis and the presence of fragmented red cells on peripheral smear. The peripheral blood contains sharply pointed poikilocytes (schistocytes). Such cells are characteristic and are clearly differentiated from abnormally shaped red cells seen in other conditions (24). The hemolysis may be severe and in such cases usually is intravascular, resulting in hemoglobinemia, hemoglobinuria, haptoglobin saturation, and subsequently hemosiderinuria (see earlier discussion). Red cell fragmentation may occur after insertion of a prosthetic, usually an aortic, valve. Rarely this is associated with clinically significant hemolysis. More often, red cell fragmentation is caused by arteriolar lesions (e.g., fibrin, inflammation) that damage the cells as they pass through the damaged vessel. When fragmented RBCs are accompanied by thrombocytopenia, one should consider the possibility of disseminated intravascular coagulation (see Chapter 56) or thrombotic thrombocytopenic purpura. This latter syndrome often is accompanied by fever and neurologic deficits, which characteristically fluctuate. If this condition is suspected, the patient should be hospitalized immediately and treated in consultation with a hematologist. The hemolytic uremic syndrome is a related (perhaps identical) syndrome, more common in children, that is characterized by the prominence of renal failure over other organ dysfunction.
Hemolysis with Enlarged Spleen (Hypersplenism)
Not all large spleens cause cytopenias, and the degree of cytopenia does not necessarily correlate with the size of the spleen (25). Thrombocytopenia and leukopenia are more common than is anemia. Splenomegaly from almost any cause may result in hypersplenism, but the syndrome is seen most often in patients who have chronic liver disease and congestive splenomegaly. Splenomegaly is sometimes seen in patients with hemolysis from other mechanisms, such as autoimmune hemolysis or hereditary spherocytosis. Rarely, splenectomy is necessary because of severe cytopenias resulting from hypersplenism. Occasionally patients with Felty syndrome (see Chapter 77) benefit from splenectomy, as do some patients with chronic leukemia or lymphoma.
Glucose-6-Phosphate Dehydrogenase Deficiency
G6PD deficiency (26) is seen primarily in African American patients in the United States. Inheritance is sex linked. Ten percent of African American males are affected (hemizygotes), as are 20% of African American females (heterozygotes). In these patients, hemolysis caused by G6PD deficiency is an acute intravascular hemolytic event usually precipitated by infection or an oxidant drug. Drugs known to precipitate hemolysis include sulfonamides, nitrofurantoin, and primaquine. Caucasian-type G6PD deficiency is seen primarily in patients from Mediterranean countries and usually is more severe than the African type. It sometimes causes chronic, persisting, partially compensated hemolysis.
Diagnosis after a hemolytic event may be difficult, especially in female heterozygotes. Screening tests for G6PD deficiency may give a normal result at this time, and even the affected hemizygote African American male may have a normal screening test for several weeks after hemolysis (young cells contain more G6PD activity). Occasionally a characteristic cell (bite cell) is seen in the peripheral blood during a hemolytic event.
Although the frequency of the genetic defect is high, the incidence of severe hemolysis with provocation (infection, drugs) is low. Ordinarily, routine screening before treatment with a known oxidant drug (e.g., sulfonamide) is not recommended. Affected patients should be given a list of drugs to avoid (26).
Sickle Cell Disorders
Approximately 8% of the African American population in the United States carry the sickle cell gene (27). The gene
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also is present to much less an extent in Greeks, Italians, Arabs, and people from India. Hemoglobin S results from a mutation in the β-globin chain in hemoglobin that, in the presence of reduced oxygen tension, causes the formation of rigid polymers that distort the shape of the RBC and increase its rigidity, leading to tissue ischemia and infarction. A number of common inherited disorders involving hemoglobin S are listed in this section.
Sickle Cell Trait
Most people who are heterozygous for hemoglobin S (sickle cell trait) are completely well and are not anemic. The peripheral smear appears normal, although sickling is seen if the blood is deoxygenated. Hemoglobin electrophoresis reveals approximately 40% hemoglobin S and 60% hemoglobin A. Hemoglobins A2 and F are present in normal concentrations.
Most patients with the sickle trait lead a normal life. However, rare clinical events attributable to the presence of sickle cell hemoglobin do occur. For example, splenic infarction at high altitudes (above 10,000 feet) has been reported. (Oxygen pressures in commercial aircraft are high enough that people with sickle cell trait may fly safely.) Occasionally, infarctions occur in more vital organs during vigorous exercise. All people with sickle cell trait have renal tubular dysfunction resulting in hyposthenuria. On occasion, severe hematuria occurs from hypertonicity in the renal medulla, resulting in sickling and leading to ischemia and tubular infarction. People with sickle cell trait have a higher incidence of renal infections, especially during pregnancy.
Identification of patients with sickle cell trait is important so that they can be given genetic counseling. A couple, both heterozygous for hemoglobin S, should be informed that they have a 25% chance of having a child with sickle cell anemia.
Sickle Cell Anemia (Hemoglobin SS)
Sickle cell anemia exists in approximately 0.15% of the African American population (27, 28, 29). The disease usually is severe and results in significant morbidity as well as a shortened life expectancy. However, survival has improved considerably in the last 30 years. Mean survival of patients with SS disease is approximately 45 years and of persons with hemoglobin SC disease is approximately 64 years (30). One of the most disturbing clinical features of the illness is the occurrence of painful vaso-occlusive episodes: recurrent episodes of severe pain, usually in the limbs and the abdomen, caused by sickling-induced ischemia. Patients have lifelong, often severe anemia, with Hct values that range from the mid-teens to the high twenties. The primary mechanism of the anemia is extravascular hemolysis. Chronic reticulocytosis and chronic indirect hyperbilirubinemia are seen. Patients usually have leukocytosis, with the white cell count occasionally rising as high as 30,000 to 40,000 cells/mm3 during a painful crisis. A mild thrombocytosis is also common. The peripheral smear shows markedly distorted red cells, including characteristically sickled cells. On electrophoresis, only hemoglobin S with a variable amount of hemoglobin F (no hemoglobin A) is detected.
The multiple and repetitive episodes of organ ischemia caused by sickling result in a host of abnormalities. The bones characteristically appear abnormal on radiography, revealing old infarctions that mimic the changes of osteomyelitis. The medullary spaces usually are widened by the marked compensatory expansion of bone marrow. The spine often takes on a distorted appearance, and aseptic necrosis of the femoral head (and, rarely, of the humeral head) is common, sometimes requiring joint replacement. Puberty often is delayed. Splenomegaly usually disappears by age 8 years because of repeated infarctions of the spleen. An adult with sickle cell anemia essentially is autosplenectomized. This lack of splenic function contributes to the propensity for infections, related especially to a decreased ability to resist pneumococcal infections. Gallstones (pigment stones) are common, and sicklers develop cholecystitis, which may be extremely difficult to differentiate clinically from a syndrome of intrahepatic cholestasis secondary to sickling in the hepatic sinusoids. There is some hazard to surgery, but patients with recurrent abdominal pain consistent with cholecystitis, who have gallstones, probably should have elective cholecystectomy (see Chapter 96). Pregnancy in women with SS disease is complicated by an increased risk for pyelonephritis, pulmonary infarction, antepartum hemorrhage, prematurity, and fetal death. With time, patients develop cardiomegaly and chronic myocardial disease related to repetitive microinfarctions of the heart. Murmurs are common and may suggest rheumatic or congenital heart disease. Patients with sickle cell anemia may develop venous thromboses and pulmonary embolism. They also may develop thromboses in situ in the lungs, followed by chronic scarring and fibrosis after many years. Pulmonary thrombosis/embolism may lead to pulmonary hypertension and right-sided heart failure. Cerebral vascular accidents, including infarction and intracerebral and subarachnoid hemorrhage, are common. Seizures are common as well. Up to 75% of patients with sickle cell anemia develop leg ulcerations that may be chronic and extremely difficult to heal. Patients with sickle cell anemia are prone to serious retinopathy, which in rare cases leads to blindness because of plugging of small retinal capillaries and subsequent neovascularization. It is important that these patients be examined yearly by an ophthalmologist because some of the problems can be
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prevented by photocoagulation of abnormal new retinal vessels (31).
Hemoglobin SC Disease
The genes that code for hemoglobin S and hemoglobin C are alleles. The C hemoglobin mutation is common in African Americans (approximately 2% prevalence), and patients doubly heterozygous for S and C constitute approximately 0.15% of that population. The syndrome is similar to that of SS disease but usually milder. In contrast to sickle cell anemia, the spleen is palpable in 50% of adult patients.
Hemoglobin S–β β-Thalassemia
Patients doubly heterozygous for hemoglobin S and β-thalassemia trait have a syndrome similar to sickle cell anemia but usually more mild. Characteristically the MCV is low. The spleen may be palpable, and hemoglobin electrophoresis reveals 70% to 80% hemoglobin S and smaller amounts of hemoglobin A and F (the reverse of the pattern in sickle cell trait).
Treatment
Vaso-Occlusive Episodes
Painful vaso-occlusive episodes often are severe and may last for a few hours to several days and occasionally for several weeks. They may be associated with high fever and neutrophilia, which makes it difficult but important to differentiate crises from infection. No specific therapy exists. Hospitalization is indicated when pain is persistent. It is important to aggressively treat patients in painful crisis. Relatively large doses of intravenous narcotics frequently are needed. Routine, rather than as-needed (p.r.n.) orders, are appropriate in the hospital. Patients with sickle cell disease metabolize narcotics rapidly, and doses must be repeated every 2 hours. Patient-controlled analgesia has been found to be useful (32). Although narcotic abuse can occur, sickle cell pain, like pain due to cancer, should be treated based on the patient's description and tolerance of the pain. The data suggest that prompt, aggressive treatment of pain decreases hospitalizations and emergency room visits (33).
Infection
Patients with sickle cell anemia are prone to infections, especially with pneumococci. Patients with sickle cell anemia should receive pneumococcal vaccine (see Chapter 18) and should be encouraged to seek medical help at the first evidence of infection or fever.
Hemolytic and Aplastic Crises
Acceleration of hemolysis is unusual in adults. An Hct that drops significantly below baseline probably is the result of decreased marrow production, associated with infection. Hemolytic episodes are much more common in children. If they occur, hospitalization and transfusion often are necessary. Patients with chronic severe hemolysis have an increased requirement for folic acid, and folic acid deficiency may occur, resulting in reticulocytopenia and more severe anemia. Therefore, daily folic acid therapy (1 mg) is reasonable for all patients with sickle cell anemia.
Thromboembolization
Patients with sickle cell disease who develop deep vein thrombosis or pulmonary embolism should be treated with anticoagulants, as should any patient with such problems (see Chapter 57). However, venography should be avoided because of the danger of development of leg ulcers in any patient with SS hemoglobin whose lower extremities are traumatized. It often is difficult to distinguish pulmonary thrombotic/embolic problems from pneumonia. The acute chest syndrome, an episode characterized by chest pain, shortness of breath, and cough—often with fever and a pulmonary infiltrate—is common in patients with sickle cell anemia and usually warrants hospitalization to evaluate the diagnostic possibilities and institute appropriate treatment. When it is associated with significant hypoxia, the syndrome can be fatal, and patients may benefit from exchange transfusion. There is evidence that use of incentive spirometry during pain crises may decrease pulmonary complications in sickle cell disease.
Leg Ulcers
Leg ulcers often are large and are particularly refractory to treatment. Skin grafting frequently is only temporarily helpful. It is important to keep the ulcers clean, to elevate the legs frequently, and to use surgical stockings and elastic wraps (see Chapter 95).
Hematuria
Patients with sickle cell trait, sickle cell anemia, SC disease, or sickle cell thalassemia are all prone to bouts of severe hematuria related to sickling and medullary ischemia precipitated by the hypertonicity of the renal medulla. Bleeding can occur for days or even weeks. Maintenance of a high urine flow is important to prevent clots from causing obstruction. Usually the hematuria stops spontaneously.
Priapism
Priapism, an undesired painful penile erection, is common in men with SS and SC disease and often results in permanent impotence once it has resolved. Urologic intervention, if attempted, must be done within a few hours of the onset of the priapism. It often is only temporarily
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helpful. Once impotence has occurred, penile protheses often are helpful (see Chapter 6).
Preventive Treatment with Hydroxyurea
A large controlled study demonstrated that treatment with hydroxyurea decreases the incidence of painful crises in some patients with sickle cell anemia (34). The mechanism may be partly (but not completely) caused by increased intracellular levels of hemoglobin F. The benefit is modest in most patients, and a therapeutic trial requires close monitoring by a hematologist. The long-term side effects of hydroxyurea must be weighed carefully before a patient is prescribed this therapy. There is a growing experience with stem cell transplantation in children with sickle cell syndromes (35).
Recommendations for Preventive Care
Patients with sickle cell disorders have a lifelong chronic illness and require frequent and recurrent use of the health care system. The patient needs one general practitioner who is familiar with his or her case. The availability of emergency care 24 hours per day is exceedingly important.
Infection
There should be rapid evaluation of fever, chills, or other signs of infection. The patient should be immunized with the pneumococcal, influenza, and Haemophilus influenzae type B vaccines (see Chapter 18). Because heart murmurs and cardiomegaly are common, determining whether a patient with sickle cell anemia has valvular heart disease may be difficult based on physical examination alone. Echocardiography is appropriate if valvular disease is suspected.
Folic Acid
It is generally recommended that patients receive 1 mg folic acid daily.
Ophthalmologic Examination
Patients should see an ophthalmologist yearly.
Transfusions
In general, transfusions should be avoided because of the dangers of iron overload, sensitization to minor red cell antigens, infection, and other hazards of transfusion. Exchange transfusion (supervised by a hematologist) may help interrupt a prolonged pain crisis and is indicated in severe, life-threatening acute chest syndrome (discussed earlier). Hypertransfusion is useful in preventing recurrent neurologic vascular events. Alloimmunization occurs much more frequently in patients with sickle cell disease than in other patients with anemia because of minor red cell antigen incompatibilities in racially mismatched blood (36). This occurrence can be minimized by routinely performing extended cross-matches using blood matched for the predominant offending antigens (Duffy, Kidd, Kell, E, C).
The question of prophylactic transfusion for patients with sickle cell disease who are undergoing surgery with a general anesthetic has been long debated. A large multicenter study suggested there is no benefit to aggressive exchange transfusion over simple preoperative transfusion to hemoglobin levels of approximately 10 g/dL (37).
Hydroxyurea
Patients with frequent, severe, life-altering, painful vaso-occlusive episodes should be referred to a hematologist for consideration for hydroxyurea therapy.
Anemias With Normal Mean Corpuscular Volume and an Inappropriately Low Reticulocyte Index
Mild normocytic anemias without appropriate reticulocyte responses are among the most common problems seen in clinical practice. Before considering possible etiologies and embarking on a diagnostic workup, it is important to be sure that Hct/Hb is reproducibly low. Moreover, the normal values for the testing laboratory should be known. For example, in some laboratories, an Hct of 35% in a woman is normal. One also should consider the variation in normal values related to age, sex, pregnancy, and other factors. Finally, one should be sure that volume overload is not the cause. Volume shifts may result in swings in Hct of six or eight percentage points. Table 55.23 lists
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the differential diagnosis of a normocytic anemia with an inappropriately low reticulocyte count.
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TABLE 55.23 Anemia with a Normal Mean Corpuscular Volume and Low Reticulocyte Index: Differential Diagnosis |
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Primary Bone Marrow Disorders
A minority of anemic patients with normal MCVs and a low reticulocyte index have primary bone marrow disorders and should be referred to a hematologist/oncologist. They require bone marrow aspiration or biopsy, and it is helpful to talk with them about the procedure before their referral visit.
Patient Experience
The procedure sounds more frightening than it is. Patients should be told that the procedure usually is done in the specialist's office and usually takes only 15 to 30 minutes. The patient lies on the side or abdomen. The usual site is the posterior superior iliac crest. A local anesthetic is used to deaden pain receptors in the dermis and periosteum. The aspirate or biopsy needles are small in diameter, and the procedure is minimally uncomfortable when done by an experienced clinician. Very anxious patients can be given an oral or parenteral analgesic, a mild sedative for anxiety, or both before the procedure if they are accompanied by someone who can drive them home. A gauze adhesive bandage (Band-Aid) is all that is used after the procedure, and acetaminophen is all that is needed for postprocedural discomfort.
Anemia of Renal Failure
Patients with uremia are anemic primarily because of decreased production of erythropoietin (38). The red cell morphology on smear usually is normal, but occasionally spiculated cells (burr cells) are seen. Some patients have a microangiopathic peripheral smear. There may be a mild thrombocytopenia, and the nuclei of the neutrophils may be hypersegmented even in the absence of folic acid deficiency. Hct depends on the degree of renal failure (see Fig. 52.4). Significant anemia is unusual if the creatinine concentration is <2 mg/100 mL. Hct values in patients with renal failure who are undergoing dialysis are extremely variable (ranging from the low teens, requiring transfusion, to the mid-thirties). Recombinant human erythropoietin is helpful for treatment of anemia of renal failure. Responses can be dramatic, and although the preparation is expensive, side effects are few (e.g., hypertension in some patients) (39). Erythropoietin levels are not reliable in predicting response to erythropoietin injections in patients with mild renal insufficiency. Patients in renal failure may be anemic because of iron deficiency (secondary to blood loss) or folate deficiency (because folic acid is dialyzable). Some patients with glomerulonephritis or arteritis have a microangiopathic hemolytic anemia.
Anemia of Chronic Disease
Any chronic inflammatory disease (e.g., rheumatoid arthritis) or malignant disease can cause mild to moderate anemia, unrelated to blood loss or hemolysis (40, 41, 42). (If the Hct is <25%, another explanation should be sought.) It is important to note that other chronic illnesses are not associated with this kind of anemia. Red cell morphology usually is normal, but sometimes the MCV is <80 fL, requiring differentiation of the process from other causes of a microcytic anemia (see earlier discussion). SI concentration and TIBC are low; the percentage of saturation may be just as low as it is in iron deficiency (<10%). The serum ferritin level is normal or elevated, and bone marrow iron stores are normal or increased. Treatment with erythropoietin sometimes is helpful in certain patients (e.g., those with cancer, human immunodeficiency infection, rheumatoid arthritis) who have severe, symptomatic anemia if the serum erythropoietin level is <500 IU/mL, and especially if it is <100 IU/mL (43, 44, 45).
In addition to chronic infections, acute infection or inflammation causes a decrease in SI, a reticulocytopenia, and a decrease in bone marrow red cell production. If present for 1 week or longer, an acute inflammatory process may result in an Hct fall of several percentage points.
Mild Early Iron Deficiency
Although severe iron deficiency results in microcytic anemia (discussed earlier), in the early stages mild iron deficiency may result in anemia with a normal peripheral smear and a normal MCV. Diagnosis usually can be made by measurement of serum ferritin or by a bone marrow iron stain. In addition, a patient with severe iron deficiency, when it accompanies a macrocytic anemia such as a megaloblastic anemia (e.g., an alcoholic patient with iron deficiency and folic acid deficiency), may have a severe anemia that is normocytic. The reticulocyte count is inappropriately low until (in the alcoholic patient) alcohol is withdrawn and iron and folate are administered.
Anemia in the Elderly
Old age per se is not an explanation for a significant normocytic anemia (46). The Hct in healthy individuals in their seventies is only slightly lower than the normal adult range (Table 55.1). However, it is in elderly patients that frustrating, mild, unexplained, normocytic anemias occur. In such patients, the following possible explanations should be considered: fluid overload, blood loss from phlebotomy if the patient has been hospitalized recently, and any recent inflammatory disease (viral or bacterial infection, inflammatory joint problem) that may depress bone marrow production and, if present for several days, may result in
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a drop in Hct. If none of these explanations seems appropriate and there is no reason to suspect an underlying problem, it is reasonable to simply monitor the Hct without further diagnostic workup. If the onset of the anemia is known to be recent (e.g., if there is a record of a normal Hct finding 3 months previously), other efforts should be made to explain the anemia. For example, the possibility of occult gastrointestinal bleeding with early iron deficiency or the anemia of chronic disease or malignancy should be entertained. There is evidence that unexplained anemias are more common in elderly poor persons with inadequate access to health care and that anemia in the very old is associated with increased mortality risk (47).
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.