This introductory chapter focuses on the general concepts of anemia, the classification of the most common types of anemia, the approach to patients with hemolysis, and the assessment of posthemorrhagic anemia. Anemia rarely is a disease by itself; almost always it is a sign of an acquired or genetic abnormality. The various medical conditions that lead to anemia encompass nearly the full spectrum of human disease.
DEFINITION OF ANEMIA
Red blood cells (RBCs) circulate in the peripheral blood for 100 to 120 days, and approximately 1% of the body’s red cells are lost and replaced each day. Red cells recognized as being old are removed from the circulation by macrophages in the spleen, liver, and bone marrow (Chapter 6)
. An erythropoietic feedback loop ensures that the total red cell mass remains constant. A reduced RBC mass results from loss of RBCs from the circulation at a rate greater than their production: this may reflect increased RBC clearance, decreased RBC production, or both.
Anemia is functionally defined as an insufficient RBC mass to adequately deliver oxygen to peripheral tissues. For practical purposes, any of the three concentration measurements performed on whole blood can be used to establish the presence of anemia: the hemoglobin (Hb) concentration, typically expressed as grams Hb per deciliter (g/dl) in the United States and as grams per liter in Europe; the hematocrit (Hct; also called the packed cell volume[PCV] or volume of packed red blood cells [vPRC]), which represents the proportion of blood volume represented by RBCs, expressed as a percent or as a decimal; and the RBC concentration in cells per microliter (106/µl) in the United States or per liter (1012/L) by international terminology.
In the past, these parameters were measured using manual physical and chemical techniques. The term “hematocrit” originally referred to the graduated tube in which the vPRC was measured following centrifugation. Now these parameters are determined by electronic cell counters and Hb analyzers (Chapter 1)
. In most of the current analyzers, RBC concentration, Hb concentration, and mean corpuscular volume (MCV in fl) are directly measured. These measured values are used to calculate the hematocrit (Hct), mean corpuscular Hb (MCH), and mean corpuscular Hb concentration (MCHC):
Hct (%) = MCV (fl) × RBC (106/µl)/10
MCH (pg) = Hb (g/dl) × 10 /(RBC (106/µl)
MCHC (%) = Hb (g/dl) × 100/Hct (%) concentration
= MCH (pg) × 100/MCV (fl)1
Most physicians prefer to define anemia using the Hb concentration, although for practical purposes the Hct is comparably reliable. The electronic counters also generate an index of red cell size, the red cell distribution width (RDW). The RDW is a quantitative measure of the variation in red cell size, and the higher the value, the more heterogeneous the RBC population size. The mean normal Hb and Hct values and the lower limits of the normal ranges of these parameters depend on the age and gender of the subjects, as well as their altitude of residence.
Anemia in Adults
Many references consider Hb concentrations of 14 g/dl and 12 g/dl as the lower limits of normal, at sea level, in adult men and women, respectively, particularly in the industrialized world.2
These values have received wide acceptance and often are used in population surveys.3
However, data from a large, diverse, and carefully selected sample suggest that these values are somewhat high. The sample studied during the second National Health and Nutrition Examination Survey (NHANES II), 1976-1980, was selected statistically as representative of the entire population of the United States.4
Age, gender, and race, as well as geographic and socioeconomic factors, were figured into the selection process. For the purpose of determining normal values, subjects were excluded if they were pregnant, if a hereditary hemoglobinopathy was detected, or if the transferrin saturation, MCV, or erythrocyte protoporphyrin value was abnormal. By these means, iron deficient subjects were effectively excluded. The values of the remaining 11,547 subjects were used to calculate a 95% reference range. In adult subjects (age 10 to 44 years), the lower limit of normal was 13.2 g/dl in men and 11.7 g/dl in women (Fig. 22.1
). Values for African-American subjects were approximately 0.5 to 0.6 g/dl lower than those of Caucasian subjects. Consistent with these observations, the World Health Organization (WHO) defines the lower limit of normal for Hb concentration at sea level to be 12.0 g/dl in women and 13.0 g/dl in men.5
FIGURE 22.1. The lower limit of normal blood hemoglobin concentration in men and women of various ages. Values were calculated from a sample of 11,547 subjects selected to represent the population of the United States. Subjects with iron deficiency, pregnancy, or an abnormal hemoglobin value were excluded from the sample. (Data from Dallman PR, Yip R, Johnson C. Prevalence and causes of anemia in the United States, 1976 to 1980. Am J Clin Nutr 1984;39(3):437-445.)
Hemoglobin Values in the Elderly
Anemia is a common condition in the older population. In a community dwelling American population of individuals over 65 years, 8.5% have a Hb concentration meeting the WHO definition of anemia.6
Other investigators have confirmed that the prevalence of anemia rises steadily with age, increasing from approximately 10% in individuals 65 years and older to 20% in individuals over 85 years.7
It is a significant predictor of morbidity, mortality, and performance status in the elderly, whether considered as a general risk factor or in the setting of a specific clinical circumstance, such as heart failure.8,9,10 and 11
While clinical conditions such as iron deficiency, B12 or folate deficiency, the decline in testosterone production in male aging,12
and the impact on EPO production of the routine decline in creatinine clearance with advancing age,8
are likely responsible for a majority of cases, the etiology of a significant proportion of these anemias cannot be readily explained.7
Studies of the development of otherwise unexplained anemia in the aging population have suggested the involvement of a number of possible mechanisms, from an increased incidence of underlying diseases which may be associated with cytokine activation and the anemia of chronic disease,13,14
to changes in the hematopoietic reserve15,16
or even in the characteristics of hematopoietic progenitors themselves.17
Taken together, slightly lower limits of normal Hb concentration may be applicable in evaluating the elderly. However, the too-easy acceptance of mild anemia as a physiologic phenomenon in the elderly runs the risk of ignoring a potentially valuable early clue to an important underlying disorder
Hemoglobin Values in Infants and Children
At the other extreme of life, the definition of anemia in infancy and childhood is different from that in adults. The lower limit of normal Hb concentration at birth is 14 g/dl, and this decreases to 11 g/dl by 1 year of age. This Hb decrement, referred to as the physiologic anemia of infancy
, occurs as part of the normal physiologic adaptation from the relatively hypoxic intrauterine existence to the well-oxygenated extrauterine environment (Chapter 43)
. Also, as fetal erythropoiesis is replaced, the MCV decreases from birth (100 to 130 fl) to 1 year of age (70 to 85 fl).
Even after the first year of life, normal childhood Hb and MCV values remain considerably lower than those occurring in adolescents and adults (Table 22.1
). From the NHANES II study, the lower limit of normal Hb concentration in both male and female children aged 1 to 2 years was 10.7 g/dl, and the value rose with advancing age until adult levels were reached at age 15 to 18 years.
There has been no completely satisfactory explanation for these differences in normal Hb values of children and adults, but it is not due to nutritional deficiencies. Interestingly, it has been demonstrated that serum inorganic phosphate is 50% higher in children compared to adults, and this hyperphosphatemia is associated with elevated erythrocyte adenosine triphosphate and 2,3-diphosphoglycerate content, and thus the erythrocyte oxygen affinity is decreased in children compared to adults. On this basis, it has been postulated that lower Hb values in children may be due to altered Hb-oxygen affinity and may thereby represent a physiologic anemia of childhood
At puberty, the Hb concentration in children reaches the same levels seen in adults. The higher Hb levels in males presumably are a reflection of the effects of androgens on erythropoiesis.
Limitations in the Use of Hemoglobin Concentration, Hematocrit, and Red Blood Cell Measurements in Defining Anemia
For practical purposes, the blood Hb and Hct determinations are equally useful in assessing for anemia in most patients, but there are limitations that must be recognized:
Hb and Hct changes may reflect altered plasma volume, not a change in RBC mass (Table 22.2
). In pregnancy, for example, the plasma volume increases, thereby decreasing the Hb concentrations, although in fact, total RBC mass actually is increased, but to a lesser degree than the plasma volume.19,20,21,22
Similarly, individuals with massive splenomegaly may have some anemia because of hypersplenism, but the degree of anemia may appear more severe because of an increased plasma volume. Conversely, burn patients lose plasma, not RBC, through the injured skin, leaving Hb and Hct concentrated at a higher level. Other causes of dehydration with depletion of intravascular space also produce a spuriously high Hb concentration. In chronically ill patients with a reduced red cell mass, the magnitude of anemia may be masked by an associated contraction of the plasma volume.23,24,25,26,27
Another consideration is that Hb and Hct changes may reflect underlying physiologic conditions with different oxygen
needs. For example, chronically hypoxemic subjects, such as individuals who live at high altitudes or patients with a rightto-left cardiac shunt, are typically polycythemic with elevated Hb/Hct levels. A normal Hb/Hct level in such a patient actually may represent anemia by the functional criterion of adequately meeting tissue oxygen requirements.
TABLE 22.1 RED BLOOD CELL CHARACTERISTICS IN CHILDHOOD
Lowest Normal Hb (g/dl)
Normal Red Blood Cell Size Mean Corpuscular Volume (fl)
Fetal Hb (%)
6 mo-1 y
TABLE 22.2 CONDITIONS ASSOCIATED WITH DISCORDANCE BETWEEN HEMOGLOBIN CONCENTRATION AND RED CELL MASS
Increase in plasma volume relative to RBC mass (Hb disproportionately low)
Hydremia of pregnancy
Recumbency (vs. upright)
Decrease in plasma volume relative to RBC mass (Hb high, normal, or low; but high relative to RBC mass)
Protracted diarrhea (especially in infants)
Peritoneal dialysis with hypertonic solutions
Diabetes insipidus with restricted fluid intake
Stress erythrocytosis, spurious polycythemia
Decrease in plasma volume and RBC mass (Hb normal, RBC mass low)
Acute blood loss
Hb, hemoglobin; RBC, red blood cell.
Some abnormal Hb variants have an altered ability to bind and release oxygen, and this can be associated with changes in Hb concentration. For example, Hb Yakima has increased oxygen affinity with a low P50, and higher than normal Hgb levels are characteristic. Conversely, Hb Kansas has decreased oxygen affinity, high P50, and lower than normal Hgb levels. Despite the disparate Hb levels in these cases, both satisfy the criteria of appropriate oxygen delivery for tissue oxygen needs.
Acute blood loss is another example of the problem of denoting anemia by the Hb concentration or Hct. Immediately after loss of a liter of blood, the Hb concentration/Hct is normal, because the initial response to acute hemorrhage is vasoconstriction. The shift of fluid from extravascular to intravascular space, and thus the decrease in Hb concentration, does not begin for 6 hours, and can continue for 48 to 72 hours. Reticulocytosis occurs after 24 to 48 hours.
Impaired partial synthesis of one globin chain, as in thalassemia trait, may be reflected in a low Hb (10 g/dl) and a high RBC count (6.5 million/µl), thus giving anemia by one measure (Hb) and erythrocytosis by another (RBC). This is largely why the RBC count is the least reliable and least commonly used indicator of anemia.
In addition to the issues listed above, changes in posture also have effects on red cell concentration that can influence Hb and Hct measurements. When normal individuals assume a recumbent position, the Hct falls an average 7% (range, 4% to 10%) within 1 hour.28
When the upright position is resumed, the Hct increases by a similar amount within 15 minutes. These changes have been attributed to alterations in plasma volume as fluid moves between the circulation and the extravascular spaces in the lower limbs as a result of hydrostatic forces.
CLINICAL EFFECTS OF ANEMIA
Patients with anemia usually seek medical attention because of decreased work or exercise tolerance, shortness of breath, palpitations, or other signs of cardiorespiratory adjustments to anemia. At times, they feel fine, but their friends or family may note pallor. It is not uncommon that anemia in a child is first recognized by a visiting relative, the process sometimes occurring so slowly as to not be noted by parents or other immediate family members.
Cardiovascular and Pulmonary Features of Anemia
The clinical manifestations of anemia depend on the magnitude and rate of reduction in the oxygen carrying capacity of the blood, the capacity of the cardiovascular and pulmonary systems to compensate for the anemia, and the associated features of the underlying disorder that resulted in the development of anemia. The Hb concentration is not the only determinant of the observed symptoms. Coexistent cardiovascular or pulmonary disease, particularly in older individuals, may exaggerate the symptoms associated with a degree of anemia that would be well tolerated under other circumstances.
If the anemia has been insidious in onset and there is no cardiopulmonary disease, the patient’s adjustment may be so effective that the blood Hb concentration may fall to 8 g/dl or even lower before the patient experiences enough symptoms to appreciate the situation.29
In cases of iron deficiency anemia, pernicious anemia, or other types of slowly developing anemia, Hb concentrations may reach levels of 6 g/dl or lower before patients are motivated to seek medical attention.30
This is particularly true in children where no limitations of physical activity may be apparent despite the existence of very severe anemia.31
The physiologic adjustments that take place with a slowly falling red cell mass chiefly involve the cardiovascular system and changes in the Hb-oxygen dissociation curve.
In many patients, respiratory and circulatory symptoms are noticeable only after exertion; however, when anemia is sufficiently severe, dyspnea and awareness of vigorous or rapid heart action may be noted even at rest. When anemia develops rapidly, shortness of breath, tachycardia, dizziness or faintness (particularly upon arising from a sitting or recumbent posture), and extreme fatigue are prominent. In chronic anemia, only moderate dyspnea or palpitation may occur, but in some patients, congestive heart failure,32
angina pectoris, or intermittent claudication33
can be the presenting manifestation. In patients with severe chronic anemia, tachycardia and postural hypotension may not be present because the total blood volume actually may be increased because of an expanded plasma volume. In the elderly particularly, cardiovascular adaptation to anemia is predominantly by increasing stroke volume, rather than by heart rate.34
It is in these cases that rapid administration of a blood transfusion may precipitate congestive heart failure by aggravating an already expanded blood volume. Concern about this possibility should not preclude expansion of the blood’s oxygen carrying capacity by transfusion if necessary; rather the judicious use of diuretics in the peritransfusion period should be considered in patients with clinical signs of volume overload.
Heart murmurs are a common cardiac sign associated with anemia. They usually are systolic in time and best heard in the pulmonic area.35,36,37
Often, they are moderate in intensity, and at times may be rough in quality and raise suspicion of organic valvular heart disease. In a study from Bosnia, 25% of the heart murmurs investigated in a pediatric cardiology clinic were attributable to anemia and resolved with its correction.38
Pallor is a sign of anemia, but many factors other than Hb concentration affect skin color. These include the degree of dilation of peripheral vessels, the degree of pigmentation, and the fluid content of the subcutaneous tissues. Certain people routinely have pale-appearing skin without being anemic. Patients with myxedema may manifest pallor without anemia. In simple vasovagal syncope, pallor results from cutaneous vasoconstriction and is not a sign of anemia. Jaundice, cyanosis, racial skin pigmentation, and dilation of the peripheral vessels all can mask the pallor of anemia.
The pallor associated with anemia is best detected in the mucous membranes of the mouth and pharynx, the conjunctivae, the lips, and the nail beds. In the hands, the skin of the palms first becomes pale, but the creases may retain their usual pink color until the Hb concentration is less than 7 g/dl.
A distinctly sallow color implies chronic anemia. A lemonyellow pallor suggests pernicious anemia, but it is observed only when the condition is well advanced. Definite pallor associated with mild scleral and cutaneous icterus suggests hemolytic anemia. Marked pallor associated with petechiae or ecchymoses suggests more generalized bone marrow failure due to acute leukemia, aplasia, or myelodysplastic syndromes.
Skin and Mucosal Changes
Other changes in the integument occur with anemia. Thinning, loss of luster, and early graying of the hair may occur, the last especially in patients with pernicious anemia, in whom it may precede the development of anemia. The nails may lose their luster, become brittle, and break easily. This finding is especially noticeable in chronic iron deficiency anemia,39
in which the nails may actually become concave instead of convex. Chronic leg ulcers may occur, especially in patients with sickle cell anemia and rarely in those with other hemolytic anemias. Glossitis occurs in association with pernicious anemia. When nutritional deficiency is associated with anemia, symmetric dermatitis may develop, fissures may be present at the angles of the mouth, glossitis may occur, and erythematous lesions on the face, neck, hands, or elbows may be found.
Headache, vertigo, tinnitus, faintness, scotomata, lack of mental concentration, drowsiness, restlessness, and muscular weakness are common symptoms of severe anemia. Paresthesias are common in pernicious anemia and may be associated with other symptoms and signs of peripheral neuropathy, and more especially with combined system disease.
A variety of ophthalmologic findings have been observed in anemic patients.40,41,42
Approximately 20% of such patients have flame-shaped hemorrhages, hard exudates, cottonwood spots, or venous tortuousness affecting the retina. The hemorrhages occur even in the absence of coexisting thrombocytopenia. Papilledema related solely to anemia has been described,43,44
and it clears when the anemia disappears.
Gastrointestinal symptoms are common in anemic patients. Some are manifestations of the underlying disorder (e.g., hiatal hernia, duodenal ulcer, or gastric carcinoma); others may be a consequence of the anemic condition, whatever its cause. Glossitis and atrophy of the papillae of the tongue commonly occur in pernicious anemia and less often in iron deficiency anemia. Painful, ulcerative, and necrotic lesions in the mouth and pharynx occur in aplastic anemia and in acute leukemia, usually reflecting the neutropenia accompanying these conditions. Dysphagia may occur in chronic iron deficiency anemia.
APPROACH TO MACROCYTIC ANEMIA
Macrocytosis is a common finding in clinical settings. In 1.7% to 3.6% of cases involving patients seeking medical care, MCV is increased, often in the absence of anemia.63,64,65,66,67,68
Mild macrocytosis (MCV of 100 to 110 fl) is particularly common and often remains unexplained, even after careful study.63
Even so, this finding should not be ignored, because it can be an important early clue to reversible disease. For example, it may appear 1 year or more before anemia develops in patients with pernicious anemia, and neurologic disease can progress during that interval.69
Morphologic and biochemical criteria allow macrocytic anemias to be divided into two groups: the megaloblastic anemias and the nonmegaloblastic macrocytic anemias. The types of macrocytic anemias clinicians encounter vary considerably depending on the population served. If alcoholism is common in the
population, it is likely to be the most common cause. In cancer patients, high MCVs are most likely due to chemotherapy. In hospitals largely serving the elderly, pernicious anemia and other nutritional anemias may predominate.68
FIGURE 22.5. Megaloblastic anemia. A: Normal red cells. B: Macroovalocytes in pernicious anemia. From Pierira I, George TI, Arber DA in Atlas of peripheral blood. Philadelphia, PA: Lippincott Williams & Wilkins, 2012. C: Hypersegmented neutrophils seen in patient with megaloblastic anemia.
When confronted with a diagnostic problem involving macrocytic anemia, the physician should first distinguish between megaloblastic and nonmegaloblastic anemia (Fig. 22.7
). The most useful steps for this purpose are morphologic examinations.
FIGURE 22.6. Peripheral blood smear. A leukoerythroblastic response seen in patient with metastatic breast cancer. From Pierira I, George TI, Arber DA in Atlas of peripheral blood. Philadelphia, PA: Lippincott Williams & Wilkins, 2012.
The term megaloblast
is a designation that was first applied by Ehrlich to the abnormal erythrocyte precursors found in the bone marrow of patients with pernicious anemia. Megaloblasts are characterized by their large size and by specific alterations in the appearance of their nuclear chromatin (Fig. 22.8
). These distinctive cells are now known to be the morphologic expression of a biochemical abnormality: retarded DNA synthesis.70
RNA synthesis remains unimpaired while cell division is restricted.71,72
As a result, cytoplasmic components, especially Hb, are synthesized in excessive amounts during the delay between cell divisions. An enlarged cell is the product of such a process. Megaloblastic anemias are defined by the presence of these cells or by other evidence of defective DNA synthesis.
A pathogenetic classification of the causes of megaloblastic anemias is presented in Table 22.4
. Most often, megaloblastic anemia is the consequence of deficiency of vitamin B12
or folate, or both. Less commonly, megaloblastic anemia results from inherited or drug-induced disorders of DNA synthesis.
Hematologic Features of Megaloblastic Anemia
Examination of the blood smear often reveals the two most valuable findings for differentiating megaloblastic from nonmegaloblastic anemia: neutrophil hypersegmentation and oval macrocytes.
Neutrophil hypersegmentation is one of the most sensitive and specific signs of megaloblastic anemia (Fig. 22.5C
). Normally, the nuclei of circulating, segmented neutrophils have fewer than five
lobes. In megaloblastic anemia, neutrophils with six or more lobes may be detected. In a large study, more than 98% of patients with megaloblastic anemia had at least one six-lobed neutrophil of the 100 cells examined, as compared with only 2% of normal control subjects.73
Hypersegmentation is among the first hematologic abnormalities to appear as the megaloblastic state develops.74
It persists for an average of 14 days after institution of specific therapy.75
FIGURE 22.7. Diagnostic approach to a patient with macrocytic anemia.
The main products of megaloblastic erythropoiesis are macrocytic erythrocytes with a distinctly oval shape. Such cells are well filled with Hb, and often central pallor is reduced or absent (Fig. 22.5B
). The oval shape may be useful in distinguishing megaloblastic anemias from other causes of macrocytosis; the macroreticulocytes that characterize accelerated erythropoiesis tend to be round and distinctly blue or gray in Romanowsky dyes.
Although oval macrocytes are prominent in megaloblastic anemia, the size and shape of the erythrocytes may vary considerably. Quantitative measures of anisocytosis, such as the RDW, are substantially increased, and the increase may precede the development of anemia.76
Morphologic changes on the blood smear, however, are most conspicuous when anemia is pronounced.
Megaloblastic anemias usually develop gradually, and the degree of anemia is often severe when first detected. Hb values less than 7 or 8 g/dl are not unusual. Macrocytosis characteristically precedes the development of anemia69,77,78
and may even do so by several years. The MCV usually is between 110 and 130 fl.
A megaloblastic marrow is cellular and usually hyperplastic, with erythrocyte precursors predominating. The characteristic megaloblasts are distinguished by their large size and especially by their delicate nuclear chromatin. The chromatin has been described as particulate or sieve-like, as distinguished from the normal denser chromatin of normoblasts (Fig. 22.8
). This morphologic change may be detected at all stages of erythrocyte development; however, the identification of orthochromatic megaloblasts is particularly useful in the recognition of megaloblastic anemia because they differ so markedly from any cell found in normal marrow. In the orthochromatic megaloblast, the abundant cytoplasm appears mature (pink), whereas the nucleus appears immature as a result of the megaloblastic change.
Leukopoiesis is also abnormal; extraordinarily large (up to 20 or 30 µm) leukocytes are found. These abnormalities of cellular development may occur at any stage in the myeloid series, but they are particularly common among the metamyelocytes. The nucleus of these giant metamyelocytes is enlarged, both absolutely and in relation to the total cell size; it may be bizarre in shape and in chromatin structure or staining properties.
In general, megakaryopoiesis is less disturbed than that of either of the other two cell lines; however, when megaloblastic change is severe, megakaryocytes may be reduced in number and abnormalities of nuclear chromatin may be evident.
FIGURE 22.8. Normoblasts and megaloblasts contrasted (Wright stain X 1000). A-E: Normoblast. A: Pronormoblast. B: Basophilic normoblast. C: Early polychromatophilic normoblast. D: Late polychromatophilic normoblast. E: Orthochromatic normoblast with stippling. F-O: Megaloblasts. F: Promegaloblast (left) and basophilic megaloblast (right). G-K: Polychromatophilic megaloblasts. L-O: Orthochromatic megaloblasts.
Vitamin B12 and Folate Levels in Serum and Erythrocytes
Once it is established that a patient has CBC and morphologic evidence of megaloblastic anemia, it should next be determined if this is due to vitamin B12
or folate deficiency (Chapter 36)
. Useful studies include measurement of serum and RBC folate levels and serum Vitamin B12
levels. Unlike serum vitamin B12
, serum folate is labile, being sensitive to short-term changes in folate balance. Thus, serum folate concentration may increase within a few hours after consumption of folate-containing food. Furthermore, a low intake of folate may result in reduced serum levels before true deficiency develops.74
The erythrocyte folate level is a much better index of tissue folate stores. Erythrocyte folate levels are established during formation of the red cell and persist throughout its lifespan. Thus, it may take 3 to 4 months of folate deprivation
before low values are obtained. Other studies such as serum homocysteine and serum methylmalonic acid can confirm a diagnosis of B12 deficiency, particularly when initial assays are at odds with the clinical and hematologic picture. Vitamin B12
absorption studies (Schilling test) or antibodies to intrinsic factor or parietal cells, can further define the specific causes of these disorders.
TABLE 22.4 PATHOGENETIC CLASSIFICATION OF MEGALOBLASTIC ANEMIA
Vitamin B12 deficiency
Dietary deficiency (rare)
Lack of intrinsic factor
Ingestion of caustic materials
Biologic competition for vitamin B12:
Small-bowel bacterial overgrowth
Fish tapeworm disease
Familial selective vitamin B12 malabsorption (Imerslund-Gräsbeck syndrome)
Drug-induced vitamin B12 malabsorption
Chronic pancreatic disease
Diseases of the ileum
Previous ileal resection
Chronic hemolytic anemia
Congenital folate malabsorption
Drug-induced folate deficiency
Extensive intestinal (jejuna) resection
Combined folate and vitamin B12 deficiency
Inherited disorders of DNA synthesis
Thiamine responsive megaloblastic anemia
Transcobalamin II deficiency
Homocystinuria and methylmalonic aciduria
Drug- and toxin-induced disorders of DNA synthesis
Folate antagonists (e.g., methotrexate)
Purine antagonists (e.g., 6-mercaptopurine)
Pyrimidine antagonists (e.g., cytosine arabinoside)
Alkylating agents (e.g., cyclophosphamide)
Zidovudine (AZT, Retrovir)
Nonmegaloblastic Macrocytic Anemias
Nonmegaloblastic anemias are not united by any common pathogenetic mechanism. They simply represent macrocytic anemias in which the RBC precursors appear normal without the characteristic nuclear and cytoplasmic findings of megaloblastosis. When macrocytosis is found, it tends to be mild; the MCV usually ranges from 100 to 110 fl and rarely exceeds 120 fl.64
Several causes of nonmegaloblastic macrocytosis are recognized (Table 22.5
Mild to moderate macrocytosis often follows erythropoietinmediated acceleration of red cell production, as may be induced by blood loss or hemolysis. In part, this increased cell size occurs because reticulocytes are approximately 20% larger than mature red cells.79
Also, under conditions of accelerated red cell production, a premature release of bone marrow reticulocytes (shift reticulocytes) occurs, and these cells are even larger and contain more RNA than normal circulating reticulocytes.80
Last, an erythroblast cell division may be skipped under this erythropoietic stress, a phenomenon that results in a macroreticulocyte that is approximately twice the normal size.81
TABLE 22.5 NONMEGALOBLASTIC MACROCYTIC ANEMIAS
Acquired sideroblastic anemia
Congenital dyserythropoietic anemia (CDA) types I and III
Spurious macrocytosis (paraproteinemia, inflammation)
Macrocytosis, usually mild, is evident in 40% to 96% of alcoholics, many of whom have no anemia.82,83,84
The finding is so characteristic of the condition that testing for macrocytosis has been used as part of the screening procedure for the detection of chronic alcohol use. It may be present in both heavy and moderate drinkers.85
Macrocytosis and anemia in alcoholic individuals have several causes. Folate deficiency can lead to megaloblastic anemia, and alcoholic cirrhosis may be associated with spur cell hemolytic anemia. Most often, however, alcoholic macrocytosis is associated with none of these factors and instead results from poorly defined direct effects of alcohol on the bone marrow. Antibodies against acetaldehyde-modified RBC protein are detected in up to 94% of alcoholics with high MCVs, but less frequently in those with normal MCVs.85
There are no morphologic stigmata of megaloblastic anemia. Serum and erythrocyte folate levels are usually normal, and the macrocytosis does not respond to folate treatment. If the patient abstains from alcohol use, the MCV returns to normal levels after 2 to 4 months.
The causes of anemia in liver disease are multifactorial, resulting from intravascular dilution due to hypervolemia, impaired ability of the marrow to respond optimally to the anemia, and in some patients, a severe hemolytic anemia associated with morphologically abnormal erythrocytes (spur cells). The anemia is usually mild to moderate. In cirrhotic patients, the Hb level averages approximately 12 g/dl, and remains above 10 g/dl in the absence of bleeding or severe hemolysis. The anemia of liver disease is mildly macrocytic: the MCV rarely exceeds 115 fl in the absence of megaloblastic changes in the bone marrow. In addition, liver disease is associated with thin macrocytes, defined as cells with increased surface area86
but without a corresponding increase in volume.87
The increased surface area of thin macrocytes is the consequence of excessive membrane lipids, especially
but also phospholipids. On the blood smear, thin macrocytes are characterized by an increased diameter and a visibly enlarged area of central pallor. The characteristic target cell of liver disease is a thin macrocyte. Because the volume of such cells is normal, their presence has no effect on the erythrocyte indices.
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