Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

80. Anemias

Kristen Cook and William L. Lyons


 Images Anemia is a group of diseases characterized by a decrease in either hemoglobin (Hb) or the volume of red blood cells (RBCs), which results in decreased oxygen-carrying capacity of the blood. Anemia is defined by the World Health Organization as Hb <13 g/dL (<130 g/L; <8.07 mmol/L) in men and <12 g/dL (<120 g/L; <7.45 mmol/L) in women.

 Images Acute-onset anemias are most likely to present with tachycardia, lightheadedness, and dyspnea. Chronic anemia often presents with weakness, fatigue, headache, vertigo, and pallor.

 Images Iron-deficiency anemia (IDA) is characterized by decreased levels of ferritin (most sensitive marker) and serum iron, as well as decreased transferrin saturation. Hb and hematocrit decrease later. RBC morphology includes hypochromia and microcytosis. Most patients are adequately treated with oral iron therapy, although parenteral iron therapy is necessary in selected patient populations.

 Images Vitamin B12 deficiency, a macrocytic anemia, can be due to inadequate intake, malabsorption syndromes, and inadequate utilization. Anemia caused by lack of intrinsic factor, resulting in decreased vitamin B12 absorption, is called pernicious anemia. Neurologic symptoms can be present and can become irreversible if the vitamin B12 deficiency is not treated promptly. Oral or parenteral therapy can be used for replacement.

 Images Folic acid deficiency, a macrocytic anemia, results from inadequate intake, decreased absorption, and increased folate requirements. Treatment consists of oral administration of folic acid, even for patients with absorption problems. Adequate folic acid intake is essential in women of childbearing age to decrease the risk of neural tube defects in their children.

 Images Anemia of inflammation (AI) is a newer term used to describe both anemia of chronic disease and anemia of critical illness. AI is a diagnosis of exclusion. It results from chronic inflammation, infection, or malignancy and can occur as early as 1 to 2 months after the onset of the disease. The serum iron level usually is decreased, but in contrast to IDA, the serum ferritin concentration is normal or increased. Treatment is aimed at correcting the underlying pathology. Anemia of critical illness occurs within days of acute illness.

 Images Anemia is one of the most prevalent clinical problems in the elderly, although not an inevitable complication of aging. Low Hb concentrations are not “normal” among elders. Anemia is associated with an increased risk of hospitalization and mortality, reduced quality of life, and decreased physical functioning in the elderly.

 Images IDA is a leading cause of infant morbidity and mortality. Age- and sex-adjusted norms must be used in the interpretation of laboratory results for pediatric patients. Primary prevention of IDA is the goal. A therapeutic trial of oral iron is the standard of care.

Anemia affects a large part of the world’s population. According to the World Health Organization, almost 1.6 billion people (25% of the world’s population) are anemic. Anemia is defined by the World Health Organization as hemoglobin (Hb) <13 g/dL (<130 g/L; <8.07 mmol/L) in men or <12 g/dL (<120 g/L; <7.45 mmol/L) in women. In the United States, about 3.5 million Americans have anemia based on self-reported data from the National Center for Health Statistics. It is estimated that millions of people are unaware they have anemia, making it one of the most underdiagnosed conditions in the United States. Iron deficiency is the leading cause of anemia worldwide, accounting for as many as 50% of cases.1 Recent data show that the overall prevalence of anemia has declined in the United States in preschool-aged children and women of childbearing age over the past 20 years, but the prevalence of IDA did not change significantly in these same groups. The reasons for these changes remain unclear.2Although nutritional deficiencies occur less often in the United States, obesity surgery, which can cause deficiencies, is becoming increasingly common. Gastric bypass may result in folate, vitamin B12, and iron deficiencies. Prevalence data are confounded by the lack of a standardized definition of anemia and lack of screening guidelines for most populations. The United States Preventive Services Task Force (USPSTF) guidelines for pregnant women recommend routine screening for IDA.

Anemia is not an innocent bystander because it can affect both length and quality of life. Retrospective observational studies of hemodialysis patients and heart failure patients suggest that anemia is an independent risk factor for mortality.3 In addition, anemia significantly influences morbidity in patients with end-stage renal disease, chronic kidney disease, and heart failure.4 Anemia is associated with psychomotor and cognitive abnormalities in children. Similarly, anemia is associated with cognitive dysfunction in patients with renal failure or cancer, and among community-dwelling elders.5 Anemia during pregnancy is associated with increased risk for low birth weights, preterm delivery, and perinatal mortality.6 Maternal IDA may be associated with postpartum depression in mothers and poor performance by offspring on mental and psychomotor tests. Global goals of treatment in anemic patients are to alleviate signs and symptoms, correct the underlying etiology, and prevent recurrence of anemia.

Images Anemia is a group of diseases characterized by a decrease in either Hb or circulating red blood cells (RBCs), resulting in reduced oxygen-carrying capacity of the blood. Anemia can result from inadequate RBC production, increased RBC destruction, or blood loss. It can be a manifestation of a host of systemic disorders, such as infection, chronic renal disease, or malignancy. Because anemia is a sign of underlying pathology, rapid diagnosis of the cause may be essential.

The functional classification of anemia is shown in Figure 80–1. This chapter focuses on the most common causes of anemia—IDA, anemia associated with vitamin B12 or folic acid deficiency, and anemia of inflammation (AI). Some of the other causes of anemia are addressed in other chapters.


FIGURE 80-1 Functional classification of anemia. Each of the major categories of anemia (hypoproliferative, maturation disorders, and hemorrhage/hemolysis) can be further subclassified according to the functional defect in the several components of normal erythropoiesis.

Characteristic changes in the size of RBCs seen in erythrocyte indices can be the first step in the morphologic classification and understanding of the anemia. Anemia can be classified by RBC size as macrocytic, normocytic, or microcytic. Vitamin B12 deficiency and folic acid deficiency both are macrocytic anemias. An example of a microcytic anemia is iron deficiency, whereas a normocytic anemia may be associated with recent blood loss or chronic disease. More than one etiology of anemia can occur concurrently. Inclusion of the underlying cause of the anemia makes diagnostic terminology easier to understand (e.g., microcytic anemia secondary to iron deficiency).

Microcytic anemias are a result of a quantitative deficiency in Hb synthesis, usually due to iron deficiency or impaired iron utilization. As a result, erythrocytes containing insufficient Hb are formed. Microcytosis and hypochromia are the morphologic abnormalities that provide evidence of impaired Hb synthesis.

Macrocytic anemias can be divided into megaloblastic and nonmegaloblastic anemias. The type of macrocytic anemia can be distinguished microscopically by peripheral blood smear examination. Megaloblasts are distinctive cells that express a biochemical abnormality of retarded DNA synthesis, resulting in unbalanced cell growth. Megaloblastic anemias may affect all hematopoietic cell lines. The most common causes of megaloblastic anemia are vitamin B12 and folate deficiency. Nonmegaloblastic macrocytic anemias may arise from liver disease, hypothyroidism, hemolytic processes, and alcoholism. Hemolytic anemias often are macrocytic, reflecting the increased numbers of circulating reticulocytes, which are larger on average than mature red cells.


In adults, RBCs are formed in the marrow of the vertebrae, ribs, sternum, clavicle, pelvic (iliac) crest, and proximal epiphyses of the long bones. In children, most bone marrow space is hematopoietically active to meet increased RBC requirements.

In normal RBC formation, a pluripotent stem cell yields an erythroid burst-forming unit. Erythropoietin (EPO) and cytokines such as interleukin-3 and granulocyte–macrophage colony-stimulating factor stimulate this cell to form an erythroid colony-forming unit in the marrow (Fig. 80–2). During this process, the nucleus becomes smaller with each division, finally disappearing in the normal erythrocyte. Hb and iron are incorporated into the gradually maturing RBC, which eventually is released from the marrow into the circulating blood as a reticulocyte. The maturation process usually takes about 1 week. The reticulocyte loses its nucleus and becomes an erythrocyte within several days. The circulating erythrocyte is a nonnucleated, nondividing cell. More than 90% of the protein content of the erythrocyte consists of the oxygen-carrying molecule Hb. Erythrocytes have a normal survival time of 120 days.7


FIGURE 80-2 Erythrocyte maturation sequence (EPO, erythropoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-3, interleukin-3).

Stimulation of Erythropoiesis

The hormone EPO, 90% of which is produced by the kidneys, initiates and stimulates the production of RBCs. Erythropoiesis is regulated by a feedback loop. The main mechanism of action of EPO is to prevent apoptosis, or programmed cell death, of erythroid precursor cells and allow their proliferation and subsequent maturation. A decrease in tissue oxygen concentration signals the kidneys to increase the production and release of EPO into the plasma, which increases production and maturation of RBCs. Under normal circumstances, the RBC mass is kept at an almost constant level by EPO matching new erythrocyte production to the natural rate of loss of RBCs. A summary of erythropoiesis is shown in Figure 80–3. Early appearance of large quantities of reticulocytes in the peripheral circulation (reticulocytosis) is an indication of increased RBC production.7


FIGURE 80-3 Physiologic regulation of red cell production by tissue oxygen tension. (Reproduced with permission from Adamson JW, Longo DL. Anemia and polycythemia. In: Longo DL, Fauci AS, Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. New York: Copyright © McGraw-Hill; 2012:

Synthesis of Hemoglobin

Hb contains a protein component with two α-chains and two β-chains. Each chain is linked to a heme group consisting of a porphyrin ring structure with an iron atom chelated at its center, which is capable of binding oxygen. The initial step in the synthesis of heme from the substrate succinyl CoA and glycine requires the presence of pyridoxine phosphate (vitamin B6) as a catalyst. Following its synthesis in the cytoplasmic mitochondria of the RBC, heme diffuses into the extramitochondrial space, where it combines with the completed α- and β-chains and forms Hb. When hemolytic destruction of RBCs exceeds marrow production capacity and anemia develops, the Hb value decreases to a steady-state level at which production is equal to destruction.

Incorporation of Iron into Heme

Iron is an essential part of Hb. The specific plasma transport protein transferrin delivers iron to the bone marrow for incorporation into the Hb molecule. Transferrin enters cells by binding to transferrin receptors, which circulate and then attach to cells needing iron. Fewer transferrin receptors are present on the surface of cells that do not need iron, thus preventing iron-replete cells from receiving excess iron.8

Circulating transferrin normally is about 30% saturated with iron. Transferrin delivers extra iron to other body storage sites, such as the liver, marrow, and spleen, for later use. This iron is stored within macrophages as ferritin or hemosiderin. Ferritin consists of a Fe3+ hydroxyphosphate core surrounded by a protein shell called apoferritin. Hemosiderin can be described as compacted ferritin molecules with an even greater iron-to-protein shell ratio. Physiologically it is a more stable, but less available, form of storage iron. Since total body iron storage is generally reflected by ferritin levels, low serum levels of ferritin provide strong evidence of IDA.9

Normal Destruction of Red Blood Cells

Phagocytic breakdown destroys older blood cells, primarily in the spleen but also in the marrow (Fig. 80–4). Amino acids from the globin chains return to an amino acid pool; heme oxygenase acts on the porphyrin heme structure to form biliverdin and to release its iron. Iron returns to the iron pool to be reused, although biliverdin is further catabolized to bilirubin. The bilirubin is released into the plasma, where it binds to albumin and is transported to the liver for glucuronide conjugation and excretion via bile. If the liver is unable to perform the conjugation, as occurs with intrinsic liver disease or oversaturation of conjugation enzymes by excessive cell hemolysis, the result is an elevated indirect (unconjugated) bilirubin. If the biliary excretion pathway for conjugated bilirubin is obstructed, an elevated direct bilirubin results. Comparison of direct and indirect bilirubin values helps to determine if the defect in bilirubin clearance occurs before or after bilirubin enters the liver. The Hb in RBCs destroyed by intravascular hemolysis becomes attached to haptoglobin and is carried back to the marrow for processing in the normal manner.10


FIGURE 80-4 Destruction of red blood cells (RBCs).


General Presentation

History, physical examination, and laboratory testing are used in the evaluation of the patient with anemia. The workup determines if the patient is bleeding and investigates potential causes of the anemia, such as increased RBC destruction, bone marrow suppression, or iron deficiency. Diet can also be important in identifying causes of anemia. Additionally, information about concurrent nonhematologic disease states and a drug history are essential when evaluating the cause of the anemia (see eChap. 23). History of blood transfusions and exposure to toxic chemicals also should be obtained.

Presenting signs and symptoms of anemia depend on its rate of development and the age and cardiovascular status of the patient. Severity of symptoms does not always correlate with the degree of anemia. Healthy patients may acclimate to very low Hb concentrations if the anemia develops slowly. Mild anemia often is associated with no clinical symptoms and may be found incidentally upon obtaining a complete blood count (CBC) for other reasons. The signs and symptoms in elderly patients with anemia may be attributed to their age or concomitant disease states. The elderly may not tolerate levels of Hb tolerated by younger persons. Similarly, patients with cardiac or pulmonary disease may be less tolerant of mild anemia. Premature infants with anemia may be asymptomatic or have tachycardia, poor weight gain, increased supplemental oxygen needs, or episodes of apnea or bradycardia.

Images Anemia of rapid onset is most likely to present with cardiorespiratory symptoms such as palpitations, angina, orthostatic lightheadedness, and breathlessness due to decreased oxygen delivery to tissues or hypovolemia in those with acute bleeding. The patient also may have tachycardia and hypotension.

If onset is more chronic, presenting symptoms may include fatigue, weakness, headache, orthopnea, dyspnea on exertion, vertigo, faintness, sensitivity to cold, pallor, and loss of skin tone. Traditional signs of anemia, such as pallor, have limited sensitivity and specificity and may be misinterpreted. With chronic bleeding, there is time for equilibration within the extravascular space, so faintness and lightheadedness are less common.

Possible manifestations of IDA include glossal pain, smooth tongue, reduced salivary flow, pica (compulsive eating of nonfood items), and pagophagia (compulsive eating of ice). These symptoms are not likely to appear unless the anemia is severe.

Neurologic findings in vitamin B12 deficiency may precede hematologic changes. Early neurologic findings may include numbness and paraesthesias. Ataxia, spasticity, diminished vibratory sense, decreased proprioception, and imbalance may occur later as demyelination of the dorsal columns and corticospinal tract develop. Vision changes may result from optic nerve involvement. Psychiatric findings include irritability, personality changes, memory impairment, depression, and, infrequently, psychosis.

Anemia associated with folate deficiency is typically macrocytic but, unlike B12 deficiency, occurs without neurological symptoms. Although the symptoms of anemia will improve with folate replacement and a partial hematologic response will occur, the neurologic manifestations of vitamin B12 deficiency will not be reversed with folic acid replacement therapy and consequently may progress or become irreversible if not treated appropriately.

Laboratory Evaluation

The initial evaluation of anemia involves a CBC (including RBC indices), reticulocyte index, and possibly an examination of a stool sample for occult blood. The results of the preliminary evaluation determine the need for other studies, such as examination of a peripheral blood smear. Based on laboratory test results, anemia can be categorized into three functional defects: RBC production failure (hypoproliferative), cell maturation ineffectiveness, or increased RBC destruction or loss (Fig. 80–1).



    • Patients may be asymptomatic or have vague complaints

    • Patients with vitamin B12 deficiency may develop neurologic consequences

    • In AI, signs and symptoms of the underlying disorder often overshadow those of the anemia


    • Decreased exercise tolerance

    • Fatigue

    • Dizziness

    • Irritability

    • Weakness

    • Palpitations

    • Vertigo

    • Shortness of breath

    • Chest pain

    • Neurologic symptoms in vitamin B12 deficiency


    • Tachycardia

    • Pale appearance (most prominent in conjunctivae)

    • Decreased mental acuity

    • Increased intensity of some cardiac valvular murmurs

    • Diminished vibratory sense or gait abnormality in vitamin B12 deficiency

Laboratory Tests

    • Hb, hematocrit (Hct), and RBC indices may remain normal early in the disease and then decrease as the anemia progresses

    • Serum iron is low in IDA and AI

    • Ferritin levels are low in IDA and normal to increased in AI

    • TIBC is high in IDA and is low or normal in AI

    • Mean cell volume is elevated in vitamin B12 deficiency and folate deficiency

    • Vitamin B12 and folate levels are low in their respective types of anemia

    • Homocysteine is elevated in vitamin B12 deficiency and folate deficiency

    • Methylmalonic acid is elevated in vitamin B12 deficiency

Figure 80–5 shows a broad, general algorithm for the diagnosis of anemia based on laboratory data. There are many exceptions and additions to this algorithm, but it can serve as a guide to the typical presentation of common types and causes of anemia. The algorithm is less useful in the presence of more than one cause of anemia.


FIGURE 80-5 General algorithm for diagnosis of anemias (↓, decreased; MCV, mean corpuscular volume; TIBC, total iron-binding capacity; WBC, white blood cells).


Values given for Hb represent the amount of Hb per volume of whole blood. The higher values seen in males are due to stimulation of RBC production by androgenic steroids, whereas the lower values in females reflect the decrease in Hb as a result of blood loss during menstruation. The Hb level can be used as a very rough estimate of the oxygen-carrying capacity of blood. Hb levels may be diminished because of a decreased quantity of Hb per RBC or because of a decrease in the actual number of RBCs.


Expressed as a percentage, hematocrit (Hct) is the actual volume of RBCs in a unit volume of whole blood. In general, it is about three times the Hb value (when Hb is expressed in g/dL). An alteration in this ratio may occur with abnormal cell size or shape and often indicates pathology. A low Hct indicates a reduction in either the number or the size of RBCs or an increase in plasma volume.

Red Blood Cell Count

The RBC count is an indirect estimate of the Hb content of the blood; it is an actual count of RBCs per unit of blood.

Red Blood Cell Indices

Wintrobe indices describe the size and Hb content of the RBCs and are calculated from the Hb, Hct, and RBC count. RBC indices, such as mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), are single mean values that do not express the variation that can occur in cells.

Mean Cell Volume (Hct/RBC Count) MCV represents the average volume of RBCs. It may reflect changes in MCH. Cells are considered macrocytic if they are larger than normal, microcytic if they are smaller than normal, and normocytic if their size falls within normal limits. Folic acid and vitamin B12 deficiency anemias yield macrocytic cells, whereas iron deficiency and thalassemia are examples of microcytic anemias. When IDA (decreased MCV) is accompanied by folate deficiency (increased MCV), the overall MCV may be normal. Failure to understand that the MCV represents an average RBC size creates the potential for overlooking some causes of the anemia.

Mean Cell Hemoglobin (Hb/RBC Count) MCH is the amount of Hb in a RBC, and usually increases or decreases with the MCV. Two morphologic changes, microcytosis and hypochromia, can reduce MCH. A microcytic cell contains less Hb because it is a smaller cell, while a hypochromic cell has a low MCH because of the decreased concentration of Hb present in the cell. Cells can be both microcytic and hypochromic, as seen with IDA. The MCH alone cannot distinguish between microcytosis and hypochromia. The most common cause of an elevated MCH is macrocytosis (e.g., vitamin B12 or folate deficiency).

Mean Cell Hemoglobin Concentration (Hb/Hct) The concentration of Hb per volume of cells is the mean cell hemoglobin concentration (MCHC). Because MCHC is independent of cell size, it is more useful than MCH in distinguishing between microcytosis and hypochromia. A low MCHC indicates hypochromia; a microcyte with a normal Hb concentration will have a low MCH but a normal MCHC. A decreased MCHC is seen most often in IDA.

Total Reticulocyte Count

The total reticulocyte count is an indirect assessment of new RBC production. It reflects how quickly immature RBCs (reticulocytes) are produced by bone marrow and released into the blood. Reticulocytes circulate in the blood about 2 days before maturing into RBCs. About 1% of RBCs are normally replaced daily, representing a reticulocyte count of 1%. The reticulocyte count in normocytic anemia can differentiate hypoproliferative marrow from a compensatory marrow response to an anemia. A lack of reticulocytosis in anemia indicates impaired RBC production. Examples include iron deficiency, B12deficiency, anemia of chronic disease (ACD), malnutrition, renal insufficiency, and malignancy. A high reticulocyte count may be seen in acute blood loss or hemolysis. The reticulocyte index can aid in determining the functional classification of an anemia (Fig. 80–5).

Red Blood Cell Distribution Width

The higher the red blood cell distribution width (RDW) is, the more variable is the size of the RBCs. The RDW increases in early IDA because of the release of large, immature, nucleated RBCs to compensate for the anemia, but this change is not specific for IDA. The RDW also can be helpful in the diagnosis of a mixed anemia. A patient can have a normal MCV yet have a wide RDW. This finding indicates the presence of microcytes and macrocytes, which would yield a “normal” average RBC size. Use of RDW to distinguish IDA from ACD is not recommended.

Peripheral Blood Smear

The peripheral blood smear can supplement other clinical data and help establish a diagnosis. Peripheral blood smears provide information on the functional status of the bone marrow and defects in RBC production. Additionally, it provides information on variations in cell size (anisocytosis) and shape (poikilocytosis). Automated blood counters, used for the CBC, can flag specific RBC changes that can be confirmed by a peripheral blood smear. Blood smears are placed on a microscope slide and stained as appropriate. Morphologic examination includes assessment of size, shape, and color. The extent of anisocytosis correlates with increased range of cell sizes. Poikilocytosis can suggest a defect in the maturation of RBC precursors in the bone marrow or the presence of hemolysis.

Serum Iron

The level of serum iron is the concentration of iron bound to transferrin. Transferrin is normally about one-third bound (saturated) to iron. The serum iron level of many patients with IDA may remain within the lower limits of normal because a considerable amount of time is required to deplete iron stores. Serum iron levels show diurnal variation (higher in the morning, lower in the afternoon), but this variation is probably not clinically significant in timing of levels.9 Since serum iron levels are decreased by infection and inflammation, serum iron levels are best interpreted in conjunction with the TIBC. The serum iron level decreases with IDA and ACD and increases with hemolytic anemias and iron overload.

Total Iron-Binding Capacity

An indirect measurement of the iron-binding capacity of serum transferrin, total iron-binding capacity (TIBC) evaluation is performed by adding an excess of iron to plasma to saturate all transferrin with iron. Each transferrin molecule can carry two iron atoms. Normally, about 30% of available iron-binding sites are filled. With this laboratory test, all binding sites are filled to measure TIBC. The excess (unbound) iron is then removed and the serum iron concentration determined. Unlike the serum iron level, the TIBC does not fluctuate over hours or days. TIBC usually is higher than normal when body iron stores are low. The finding of a low serum iron level and a high TIBC suggests IDA. The TIBC is actually a measurement of protein serum transferrin, which can be affected by a variety of factors. Patients with infection, malignancy, inflammation, liver disease, and uremia may have a decreased TIBC and a decreased serum iron level, which are consistent with the diagnosis of ACD.

Percentage Transferrin Saturation

The ratio of serum iron level to TIBC indicates transferrin saturation. It reflects the extent to which iron-binding sites are occupied on transferrin and indicates the amount of iron readily available for erythropoiesis. It is expressed as a percentage, as described in the following formula:


Transferrin normally is 20% to 50% saturated with iron. In IDA, transferrin saturation of 15% or lower is commonly seen.10 Transferrin saturation is a less sensitive and specific marker of iron deficiency than are ferritin levels.

Serum Ferritin

The serum concentration of ferritin (storage iron) is proportional to total iron stores and therefore is the best indicator of iron deficiency or iron overload. Ferritin levels indicate the amount of iron stored in the liver, spleen, and bone marrow cells. Low serum ferritin levels are virtually diagnostic of IDA. In contrast, serum iron levels may decrease in both IDA and ACD. Serum ferritin is an acute phase reactant; so chronic infection or inflammation can increase its concentration independent of iron status, masking depleted tissue stores. This limits the utility of the serum ferritin if the level is normal or high for a chronically ill patient. For these patients, iron, even if present in these tissue stores, may not be available for erythropoiesis.

Soluble Transferrin Receptor

The soluble transferrin receptor (sTfR) assay is a laboratory test considered a sensitive, early, highly quantitative marker of iron depletion. The sTfR concentration is inversely correlated with tissue iron stores, and elevated levels are predictive of iron deficiency. Unlike ferritin, the sTfR is not an acute phase reactant; so its level remains normal for patients with chronic disease. It may be a useful test for distinguishing ACD from IDA.9 The major limitation of this test is that it is not widely available in many laboratories.

Folic Acid

The results of folic acid measurements vary depending on the assay method used. Decreased serum folic acid levels indicate a folate deficiency megaloblastic anemia that may coexist with a vitamin B12deficiency anemia. Erythrocyte folic acid levels are less variable than serum levels because they are slow to decrease in an acute process such as drug-induced folic acid deficiency and slow to increase with oral folic acid replacement. In addition, erythrocyte folic acid levels have the theoretical advantage of less susceptibility to rapid changes in diet and alcohol intake. Limitations with sensitivity and specificity do exist with measurements of erythrocyte folate. It has been proposed that serum folate assay levels be drawn for patients with MCV >110 fL or for patients with a lower MCV and clinical features suggesting a macrocytic anemia. If the serum folate concentration is normal for a patient with suspected folate deficiency, then the erythrocyte folate level should be measured.11

Vitamin B12

Low levels of vitamin B12 (cyanocobalamin or cobalamin) indicate deficiency. However, a deficiency may exist prior to the recognition of low serum levels. Serum values are maintained at the expense of vitamin B12 tissue stores. Vitamin B12 and folate deficiency may overlap, thus serum levels of both vitamins should be determined. Vitamin B12 levels may be falsely low with folate deficiency, pregnancy, and use of oral contraceptives.12

Schilling Test

This test used to be the “gold standard” for assessing vitamin B12 absorption. Due to its cost, unavailable test components, and complexity, the test is rarely used today. Tests to replace it are under investigation.13


Vitamin B12 and folate both are required for conversion of homocysteine to methionine. Increased serum homocysteine may suggest vitamin B12 or folate deficiency. Homocysteine levels also can be elevated in patients with vitamin B6 deficiency, renal failure, hypothyroidism, or a genetic defect in cystathionine β-synthase.14

Methylmalonic Acid

A vitamin B12 coenzyme is needed to convert methylmalonyl coenzyme A to succinyl coenzyme A. Patients with vitamin B12 deficiency have increased concentrations of serum methylmalonic acid (MMA), which is a more specific marker for vitamin B12 deficiency than homocysteine. MMA levels are not elevated in folate deficiency because folate does not participate in MMA metabolism. Levels of both MMA and homocysteine usually are elevated prior to the development of hematologic abnormalities and reductions in serum vitamin B12 levels.12 MMA levels must be interpreted cautiously for patients with renal disease and hypovolemia because the levels may be elevated due to decreased urinary excretion.



Iron deficiency is the most common nutritional deficiency in developing and developed countries. Data from the National Health and Nutrition Examination Survey (NHANES) indicate the prevalence of IDA in young children and women of childbearing age is 1.2% and 4.5%, respectively.2 The normal ranges for Hb and Hct are so wide that a patient may lose up to 15% of RBC mass and still have a Hct within the normal range. Therefore, iron deficiency may precede the appearance of anemia.

Iron Balance

The normal iron content of the body is about 3 to 4 g. Iron is a component of Hb, myoglobin, and cytochromes. About 2 g of the iron exists in the form of Hb, and about 140 mg exists as iron-containing proteins such as myoglobin. About 3 mg of iron is bound to transferrin in plasma, and 1,000 mg of iron exists as storage iron in the form of ferritin or hemosiderin. The rest of the iron is stored in other tissues such as cytochromes.9 Due to the toxicity of inorganic iron, the body has an intricate system for iron absorption, transport, storage, assimilation, and elimination. Hepcidin is a regulator of intestinal iron absorption, iron recycling, and iron mobilization from hepatic stores. It is a peptide made in the liver, distributed in plasma, and excreted in urine. Hepcidin inhibits efflux of iron through ferroportin. Hepcidin synthesis is increased by iron loading and decreased by anemia and hypoxia. Hepcidin is induced during infections and inflammation, which allows iron to sequester in macrophages, hepatocytes, and enterocytes.15 As a result, hepcidin is likely an important mediator of AI. Hepicidin is usually suppressed in IDA.16

Most people lose about 1 mg of iron daily. Menstruating women can lose up to 0.6% to 2.5% more per day. Pregnancy requires an additional 700 mg of iron and a blood donation can result in as much as 250 mg of iron loss;17these patients are at higher risk for deficiency.

Iron is best absorbed in its ferrous (Fe2+) form. The normal daily Western diet contains mainly the ferric (Fe3+) nonabsorbed form. After iron is ionized by stomach acid and then reduced to the Fe2+ state, it is absorbed primarily in the duodenum, and to a smaller extent in the jejunum, via intestinal mucosal cell uptake. Subsequently, it is transferred across the cell into the plasma. Iron absorption is not directly proportional to iron intake. Rather as physiologic iron levels decrease, GI absorption of iron increases.

The daily recommended dietary allowance for iron is 8 mg in adult males and postmenopausal females and 18 mg in menstruating females. Children require more iron because of growth-related increases in blood volume, and pregnant women have an increased iron demand brought about by fetal development. In the absence of hemochromatosis, iron overload does not occur, because only the amount of iron lost per day is absorbed. The amount of iron absorbed from food depends on the body stores, the rate of RBC production, the type of iron provided in the diet, and the presence of any substances that may enhance or inhibit iron absorption.

Heme iron, which is found in meat, fish, and poultry, is about three times more absorbable than the nonheme iron found in vegetables, fruits, dried beans, nuts, grain products, and dietary supplements. Gastric acid and other dietary components such as ascorbic acid increase the absorption of nonheme iron. Dietary components that form insoluble complexes with iron (phytates, tannates, and phosphates) decrease absorption. Phytates, a natural component of grains, brans, and some vegetables, can form poorly absorbed complexes and partially explain the increased prevalence of IDA in poorer countries, where grains and vegetables compose a disproportionate amount of the normal diet. Polyphenols bind iron and decrease nonheme iron absorption when large amounts of tea or coffee are consumed with a meal. Although the mechanism is unknown, calcium inhibits absorption of both heme and nonheme iron. Finally, because gastric acid improves iron absorption, patients who have undergone a gastrectomy or have achlorhydria have decreased iron absorption.18


Iron deficiency results from prolonged negative iron balance, which can occur due to increased iron demand or hematopoiesis, increased loss, or decreased intake/absorption. The onset of iron deficiency depends on an individual’s initial iron stores and the imbalance between iron absorption and loss. Multiple etiologic factors usually are involved. Certain groups at higher risk for iron deficiency include children younger than 2 years, adolescent girls, pregnant/lactating females, and those older than 65 years. Patients older than 65 years of age with IDA should be considered for testing for occult GI bleeding.17Blood loss must initially be considered a cause of IDA in adults. Blood loss may occur as a result of many disorders, including trauma, hemorrhoids, peptic ulcers, gastritis, GI malignancies, arteriovenous malformations, diverticular disease, copious menstrual flow, nosebleeds, and postpartum bleeding. In less industrialized nations, the risk of IDA is largely related to dietary factors.

The USPSTF recommends routine screening for IDA in all pregnant women.19 The USPSTF has concluded that evidence is insufficient to recommend for or against routine iron supplementation for nonanemic pregnant women.17 However, iron deficiency in pregnant women is so common that the Centers for Disease Control and Prevention (CDC) guidelines recommend initiation of low-dose iron supplements or prenatal vitamins with 30 mg/day of iron at each woman’s first prenatal visit.

Medication history, specifically regarding recent or past use of iron, alcohol, corticosteroids, warfarin or other anticoagulants, aspirin, and nonsteroidal antiinflammatory drugs (NSAIDs), is a vital part of the history to assess bleeding risk. Other possible causes of hypochromic microcytic anemia include AI, thalassemia, sideroblastic anemia, and heavy metal (mostly lead) poisoning (Fig. 80–4).


Iron is vital to the function of all cells. Without iron, cells lose their capacity for electron transport and energy metabolism. Iron deficiency usually is the result of a long period of negative iron balance. Manifestations of iron deficiency occur in three stages. In the initial stage, iron stores are reduced without reduced serum iron levels and can be assessed with serum ferritin measurement. The stores allow iron to be utilized when there is an increased need for Hb synthesis. Once stores are depleted, there still is adequate iron from daily RBC turnover for Hb synthesis. Further iron losses would make the patient vulnerable to anemia development. In the second stage, iron deficiency occurs when iron stores are depleted, and Hb is above the lower limit of normal for the population but may be reduced for a given patient. This can be determined by serial CBC measurements. Findings include reduced transferrin saturation and increased TIBC. The third stage occurs when the Hb falls to less than normal values.

Laboratory Findings

Images Abnormal laboratory findings for patients with IDA generally include low serum iron and ferritin levels and high TIBC. In the early stages of IDA, RBC size is not changed. Low ferritin concentration is the earliest and most sensitive indicator of iron deficiency. However, ferritin may not correlate with iron stores in the bone marrow because renal or hepatic disease, malignancies, infection, or inflammatory processes may increase ferritin values.9 Hb, Hct, and RBC indices usually remain normal in early stages.

In the later stages of IDA, Hb and Hct fall below normal values, and a microcytic hypochromic anemia develops. Microcytosis may precede hypochromia, as erythropoiesis is programmed to maintain normal Hb concentration in preference to cell size. As a result, even slightly abnormal Hb and Hct levels may indicate significant depletion of iron stores and should not be ignored. In terms of RBC indices, MCV is reduced earlier in IDA than Hb concentration.

Transferrin saturation (i.e., serum iron level divided by the TIBC) is useful for assessing IDA. Low values may indicate IDA, although low serum transferrin saturation values also may be present in inflammatory disorders. The TIBC may help to differentiate the diagnosis in these patients: TIBC >400 mcg/dL (71.6 mol/L) suggests IDA, while values <200 mcg/dL (35.8 mol/L) usually represent inflammatory disease.


Iron Deficiency Anemia

Desired Outcomes

The outcomes for all types of anemia in this chapter include: reversal of hematologic parameters to normal, return of normal function and quality of life, and prevention or reversal of long-term complications such as neurologic complications of vitamin B12 deficiency.

Dietary Supplementation and Oral Iron Preparations

The severity and cause of IDA determine the approach to treatment. Treatment is focused on replenishing iron stores. Because iron deficiency can be an early sign of other illnesses, treatment of the underlying disease may aid in the correction of iron deficiency.

Treatment of IDA usually consists of dietary supplementation and administration of oral iron preparations. Foods high in iron are listed in Table 80–1. Iron is best absorbed from meat, fish, and poultry. These foods as well as certain iron-fortified cereals can help treat IDA. Orange juice and other ascorbic acid-rich foods can be included with meals to increase absorption. Milk and tea reduce absorption and should be consumed in moderation. In most cases of IDA, oral administration of iron therapy with soluble Fe2+ iron salts is appropriate.

TABLE 80-1 Good Sources of Iron


Fe2+ sulfate, succinate, lactate, fumarate, glutamate, and gluconate are absorbed similarly. The addition of copper, cobalt, molybdenum, or other minerals provides no advantage but increases cost of the product. Iron is best absorbed in the reduced Fe2+ form, with maximal absorption occurring in the duodenum, primarily due to the acidic medium of the stomach. Slow-release or sustained-release iron preparations do not undergo sufficient dissolution until they reach the small intestine. In the alkaline environment of the small intestine, iron tends to form insoluble complexes, which significantly reduces absorption. The dose of iron replacement therapy depends on the patient’s ability to tolerate the administered iron. Tolerance of iron salts improves with a small initial dose and gradual escalation to the full dose. For patients with IDA, the generally recommended dose is about 150 to 200 mg of elemental iron daily, usually in two or three divided doses to maximize tolerability. If patients cannot tolerate this daily dose of elemental iron, smaller amounts of elemental iron (e.g., single 325 mg tablet of Fe2+ sulfate) usually are sufficient to replace iron stores, although at a slower rate. Table 80–2 lists the percentage of elemental iron of commonly available iron salts. The percentage of iron absorbed decreases progressively as the dose increases, although the absolute amount absorbed increases. Iron preferably is administered at least 1 hour before meals because food can interfere with iron absorption. Many patients must take iron with food because they experience GI upset when iron is administered on an empty stomach.

TABLE 80-2 Oral Iron Products


Clinical Controversy…

Daily ferrous sulfate is not tolerated by all patients and can be difficult to administer in populations of developing countries. Weekly rather than daily supplements have been used, with conflicting efficacy results. The weekly approach follows the natural pattern of mucosal cell turnover.

Adverse reactions to therapeutic doses of iron are primarily GI in nature and consist of dark discoloration of feces, constipation or diarrhea, nausea, and vomiting. GI side effects usually are dose related and are similar among iron salts when equivalent amounts of elemental iron are administered. Administration of smaller amounts of iron with each dose or administration with meals may minimize these adverse effects. Histamine-2 blockers or proton-pump inhibitors reduce gastric acidity and may impair iron absorption. Table 80–3 lists drug interactions with iron.

TABLE 80-3 Iron Salt-VDrug Interactions


Failure to respond to appropriate treatment regimens necessitates reevaluation of the patient’s condition. A “therapeutic trial of iron” approach will occasionally be used to confirm a presumptive diagnosis of IDA. Common causes of treatment failure include poor patient adherence, inability to absorb iron, incorrect diagnosis, continued bleeding, or a concurrent condition that impairs full reticulocyte response. Even when iron deficiency is present, response may be impaired when a coexisting cause for anemia exists. Rarely a patient has diminished ability to absorb iron, most often due to previous gastrectomy, such as gastric bypass surgery, or celiac disease. Regardless of the form of oral therapy used, treatment should continue for 3 to 6 months after the anemia is resolved to allow for repletion of iron stores and to prevent relapse. Patients should be instructed to store oral iron out of reach of children and pets as small amounts can result in a fatal overdose. Products containing more than 30 mg of elemental iron are required to be packaged as individual dosage units to prevent toxicity. Treatment for acute iron poisoning is discussed in eChapter 10.

Parenteral Iron Therapy

Indications for parenteral iron therapy include intolerance to oral, malabsorption, and long-term nonadherence. Patients with significant blood loss who refuse transfusions and cannot take oral iron therapy also may require parenteral iron therapy. Parenteral iron therapy is also used for patients with chronic kidney disease (see Chap. 29), especially those undergoing hemodialysis, and for some cancer patients receiving chemotherapy on erythropoiesis-stimulating agents (ESAs; see Chap. 104). Four different parenteral iron preparations currently available in the United States are iron dextran, sodium ferric gluconate, iron sucrose, and ferumoxytol (Table 80–4). They differ in their molecular size, pharmacokinetics, bioavailability, and adverse effect profiles. Although toxicity profiles of these agents differ, clinical studies indicate that each is efficacious. Most of the recent research on IV iron has been performed in hemodialysis patients. Iron dextran parenteral preparations have been associated with more anaphylactic reactions. The safety profile of parenteral iron is largely assessed by spontaneous reports to the FDA and observational studies. All parenteral iron preparations carry a risk for anaphylactic reactions but likely to a lesser extent than iron dextran.20,21 A concern with parenteral iron is that iron may be released too quickly and overload the ability of transferrin to bind it, leading to free iron reactions that can interfere with neutrophil function. In regards to general estimation of total dose of parenteral iron needed to correct anemia, the following formula can be used:

TABLE 80-4 Comparison of Parenteral Iron Products



An additional quantity of iron to replenish stores should be added (about 600 mg for women and 1,000 mg for men).9

Iron dextran, a complex of Fe3+ hydroxide and the carbohydrate dextran, contains 50 mg of iron per milliliter and can be given via the intramuscular or IV route. Different brands of iron dextran are available and differ in their molecular weight. They are not interchangeable. Iron dextran must be processed by macrophages for the iron to be biologically available. The absorption and metabolism vary with the route and amount of drug given. The intramuscular route is no longer used routinely.22 The intramuscular administration of iron dextran requires the Z-tract injection technique to minimize staining of the skin and pain. This technique is used for delivering intramuscular injections of irritating substances to minimize tracking of the medication through surrounding tissues. If intramuscular doses are given, they should not exceed 25 mg for patients weighing less than 5 kg, 50 mg for patients weighing less than 10 kg, and 100 mg for all other patients. Problems with intramuscular administration include patient discomfort, unpredictable delivery, sterile abscesses, tissue necrosis, and atrophy.23

The iron dextran package insert carries a black-box warning regarding the risk of anaphylaxis. A test dose is required prior to administration of any dose. Fatal reactions have also occurred in patients who tolerated the test dose. The European Medicines Agency is currently considering recommendations to not require a test dose for any parenteral iron preparation. This is based on data that has shown test doses were not necessarily predictive of those that would have anaphylactic reactions. The United States labeling still recommends this with iron dextran at this time. Patients with a history of multiple drug allergies and those who are concomitantly taking angiotensin-converting enzyme inhibitors may be at higher risk. The anaphylactic reactions may be more common with the high molecular weight iron dextrin product.24 Patients should also be monitored throughout the complete administration of iron dextran and resuscitative equipment should be readily available. Methods of IV administration include multiple slow injections of undiluted iron dextran solution or an infusion of a diluted preparation. This latter method often is referred to as total dose infusion.

Equations for calculating the appropriate doses of parenteral iron dextran for patients with IDA or anemia secondary to blood loss are listed in Table 80–5. Doses given by IV administration should not exceed 50 mg of iron per minute (1 mL/min). It is suggested that all patients considered for an iron dextran injection receive a test dose of 25 mg intramuscularly or IV or a 5- to 10-minute infusion of the diluted solution. Patients should then be observed for more than 1 hour for untoward reactions. An anaphylaxis-like reaction generally responds to IV epinephrine, diphenhydramine, and corticosteroids. If the test dose is tolerated, patients receiving total dose infusions can receive infusion of the remaining solution during the next 2 to 6 hours.23

TABLE 80-5 Equations for Calculating Doses of Parenteral Iron Dextran


Total replacement doses of IV iron dextran have been given as a single dose. A test dose still is required. The ability to give a total dose infusion is a benefit of iron dextran over the other parenteral iron products.17 This is not an FDA approved way of administering iron dextran. Iron dextran is best utilized when smaller frequent doses of sodium ferric gluconate or iron sucrose are impractical. Patients who receive total dose infusions are at higher risk for adverse reactions, such as arthralgias, myalgias, flushing, malaise, and fever. Other adverse reactions of iron dextran include staining of the skin, pain at the injection site, allergic reactions, and rarely anaphylaxis. Patients with preexisting immune-mediated diseases, such as active rheumatoid arthritis or systemic lupus erythematosus, are considered at high risk for adverse reactions because of their hyperreactive immune response.

Sodium ferric gluconate is a complex of iron bound to one gluconate and four sucrose molecules in a repeating pattern. Its molecular weight is 289 to 440 kDa. Sodium ferric gluconate is available in an aqueous solution. No direct transfer of iron from the Fe3+ gluconate to transferrin occurs. The complex is taken up quickly by the mononuclear phagocytic system and has a half-life of about 1 hour in the bloodstream. Sodium ferric gluconate appears to produce fewer anaphylactic reactions than iron dextran does. Side effects of sodium ferric gluconate include cramps, nausea, vomiting, flushing, hypotension, intense upper gastric pain, rash, and pruritus.25

Iron sucrose is a polynuclear iron(III) hydroxide in sucrose complex with a molecular weight of 34 to 60 kDa. It is available in 5 mL single-dose vials. Each vial contains 100 mg (20 mg/mL) of iron sucrose. Following IV administration of iron sucrose, the iron is released directly from the circulating iron sucrose to transferrin and is taken up by the mononuclear phagocytic system and metabolized. The half-life is about 6 hours, with a volume of distribution similar to that of iron dextran. Iron sucrose injection should not be administered concomitantly with oral iron preparations because it will reduce the absorption of oral iron.26 Adverse effects include leg cramps and hypotension.

Ferumoxytol is the newest FDA-approved parenteral product to treat iron deficiency in adults with chronic kidney disease who are on or off dialysis. Ferumoxytol can be administered at a quicker rate than other parenteral iron products with a rate up to 30 mg/s. Typical dosing is 510 mg IV dose followed by a second 510 mg dose 3 to 8 days later. The dose can be readministered after 1 month if anemia persists. No test dose is required but anaphylaxis can occur and patients should be observed for at least 30 minutes after each dose. Compared with oral iron replacement therapy, ferumoxytol has a higher incidence of hypotension and dizziness but less diarrhea, nausea, constipation, and peripheral edema. Clinical experience with this new preparation is still accumulating as it is still relatively new to the market.27


Macrocytic anemias are divided into megaloblastic and nonmegaloblastic anemias. Macrocytosis, as seen in megaloblastic anemias, is caused by abnormal DNA metabolism resulting from vitamin B12 or folate deficiency. It also can be caused by administration of various drugs, such as hydroxyurea, zidovudine, cytarabine, methotrexate, azathioprine, 6-mercaptopurine, and cladribine. In vitamin B12- or folate-deficiency anemia, megaloblastosis results from interference with folic acid- and vitamin B12-interdependent nucleic acid synthesis in the immature erythrocyte. The rate of RNA and cytoplasm production exceeds the rate of DNA production. The maturation process is retarded, resulting in immature large RBCs (macrocytosis). RNA and DNA synthesis depend on a series of reactions catalyzed by vitamin B12and folic acid because of their role in the conversion of uridine to thymidine. As shown in Figure 80–6, dietary folates are absorbed in this process and converted to 5-methyl-tetrahydrofolate (A), which then is converted via a B12-dependent reaction (B) to tetrahydrofolate (C). After gaining a carbon, tetrahydrofolate is converted to 5,10-methyl-tetrahydrofolate (D), a folate cofactor used by thymidylate synthetase (E) in the biosynthesis of nucleic acids. The 5,10-methyl-tetrahydrofolate cofactor is converted to dihydrofolate (F) during biosynthesis. Dihydrofolate reductase normally reduces dihydrofolate back to tetrahydrofolate (C), which can again pick up a carbon and be recycled to produce more 5,10-methyl-tetrahydrofolate (D).


FIGURE 80-6 Drug-induced megaloblastosis (DHF, dihydrofolate; 5-MTHF, 5-methyl-tetrahydrofolate; 5,10-MTHF, 5,10-methyl-tetrahydrofolate; THF, tetrahydrofolate).

Although vitamin B12 and folate deficiency are common causes of macrocytosis, other possible causes must be considered if these deficiencies are not found. Other causes of macrocytosis include (1) a shift to immature or stressed RBCs as seen in reticulocytosis, aplastic anemia, and pure RBC aplasia; (2) a primary bone marrow disorder such as myelodysplastic syndromes, congenital dyserythropoietic anemias, and large granular lymphocyte leukemia; (3) lipid abnormalities as seen with liver disease, hypothyroidism, or hyperlipidemia; and (4) unknown mechanisms resulting from alcohol abuse and multiple myeloma. Macrocytosis is the most typical morphologic abnormality associated with excessive alcohol consumption. Even with adequate folate and vitamin B12 levels and the absence of liver disease, patients with high alcohol intake may present with an alcohol-induced macrocytosis. Cessation of alcohol ingestion results in resolution of the macrocytosis within a couple of months.

Vitamin B12 Deficiency Anemia

The prevalence of vitamin B12 deficiency anemia in the United States is unknown. Risk increases with age.28 Increased use of gastric acid-suppressing agents, which may inhibit cobalamin release from food, is associated with an increased risk. Older adults in the United States have a high prevalence (up to 15%) of elevated MMA levels and associated low or low-normal vitamin B12 levels, likely due to atrophic gastritis and malabsorption of food-bound vitamin B12.27


Images The three major causes of vitamin B12 deficiency are inadequate intake, malabsorption syndromes, and inadequate utilization. Inadequate dietary consumption of vitamin B12 is rare. It usually occurs only in patients who are strict vegans and their breast-fed infants, chronic alcoholics, and elderly patients who consume a “tea and toast” diet because of financial limitations or poor dentition. Decreased vitamin B12 absorption can occur with loss of intrinsic factor by autoimmune mechanisms (such as pernicious anemia, in which gastric parietal cells are selectively damaged), chronic atrophic gastritis, or stomach surgery. One of the most frequent causes of low serum B12 levels is maldigestion, which results from the inability of vitamin B12 to be cleaved and released from proteins in food because of inadequate gastric acid production. Treatment of Helicobacter pylori may improve vitamin B12 status because this bacterial infection is a cause of chronic gastritis.29 Vitamin B12 deficiency may occasionally result from overgrowth of bacteria in the bowel that use vitamin B12 or from injury or removal (from Crohn’s disease or small bowel surgery, respectively) of ileal receptor sites where vitamin B12 and the intrinsic factor complex are absorbed. Blind loop syndrome, Whipple disease, Zollinger–Ellison syndrome, tapeworm infestations, intestinal resections, tropical sprue, surgical resection of the ileus, pancreatic insufficiency, inflammatory bowel disease, advanced liver disease, tuberculosis, and Crohn’s disease may contribute to the development of vitamin B12 deficiency.28


Vitamin B12 works closely with folate in the synthesis of building blocks for DNA and RNA, is essential in maintaining the integrity of the neurologic system, and plays a role in fatty acid biosynthesis and energy production. It is a water-soluble vitamin obtained exogenously by ingestion of meat, fish, poultry, dairy products, and fortified cereals. The body stores several years of vitamin B12, of which about 50% is in the liver. The recommended daily allowance is 2 mcg in adults and 2.6 mcg in pregnant or breast-feeding women. The average western diet provides 5 to 15 mcg of vitamin B12 daily, of which 1 to 5 mcg is absorbed.28 Vitamin B12 deficiency usually takes several years to develop following vitamin deprivation.

Once dietary cobalamin enters the stomach, pepsin and hydrochloric acid release the cobalamin from animal proteins. The free cobalamin then binds to R-protein, which is released from parietal and salivary cells. In the duodenum, the cobalamin–R-protein complex is degraded, releasing free cobalamin. The cobalamin then binds with intrinsic factor that serves as a cell-directed carrier protein similar to transferrin for iron. This complex attaches to mucosal cell receptors in the distal ileum, the intrinsic factor is discarded, and the cobalamin is bound to transport proteins (transcobalamin I, II, and III). The cobalamin bound to transcobalamin II is secreted into the circulation and is taken up by the liver, bone marrow, and other cells. Most circulating cobalamin is bound to transcobalamin I and transcobalamin III. Passive diffusion is an alternate pathway for vitamin B12 absorption independent of intrinsic factor or an intact terminal ileum and accounts for about 1% of vitamin B12 absorption.28

Vitamin B12 deficiency can cause neurologic and hematologic complications. These usually start with bilateral paraesthesia in extremities; deficits in proprioception and vibration can also be present. If not treated, this can progress to ataxia, dementia-like symptoms, psychosis, and vision loss. In children prolonged deficiency can lead to poor brain development.13,30 Patients with unexplained neuropathies should be evaluated for vitamin B12deficiency.

Laboratory Findings

In macrocytic anemias, MCV is elevated >100 fL, but some patients deficient in vitamin B12 may have a normal MCV. If there is a coexisting cause of microcytosis, the MCV may not be elevated.30 Mild leukopenia and thrombocytopenia are often present because abnormal DNA synthesis can affect all blood cell lines. A peripheral blood smear demonstrates macrocytosis accompanied by hypersegmented polymorphonuclear leukocytes (one of the earliest and most specific indications of this disease), oval macrocytes, anisocytosis, and poikilocytosis. Serum lactate dehydrogenase and indirect bilirubin levels may be elevated as a result of hemolysis or ineffective erythropoiesis.13 Other laboratory findings include a low reticulocyte count, low serum vitamin B12 level (<150 pg/mL [<111 pmol/L]), and low Hct.

In the early stages of vitamin B12 deficiency, classic signs and symptoms of megaloblastic anemia may not be evident, and serum levels of vitamin B12 may be within normal limits. Therefore, measurement of MMA and homocysteine may be useful because these parameters are typically the first to change. Because MMA and homocysteine are involved in enzymatic reactions that depend on vitamin B12, a deficiency in vitamin B12 leads to accumulation of these metabolites. Elevations in MMA are more specific for vitamin B12 deficiency. Homocysteine is also elevated in several other situations including: folate deficiency, chronic renal disease, alcoholism, smoking, use of steroid or cyclosporine therapy, and smoking.30 Low levels of vitamin B12 result in hyperhomocysteinemia, which some studies have reported to be an independent risk factor for cerebrovascular, peripheral vascular, coronary, and venous thromboembolic disease.31

Blood levels of vitamin B12 should be drawn for all patients with suspected vitamin B12 deficiency. Vitamin B12 values <150 to 200 pg/mL (<111 to 148 pmol/L) are suggestive of B12 deficiency. Some patients with clinical B12deficiency manifesting as neurological disease may have normal hematological parameters. Subclinical vitamin B12 deficiency is sometimes referred to with vitamin B12 levels 200 to 300 pg/mL (148 to 221 pmol/L).32 A general multivitamin does not typically contain enough vitamin B12 to normalize levels in deficient persons. Whether to treat patients in this range is not clear in the absence of neurologic symptoms.

A Schilling test may theoretically be performed to diagnose pernicious anemia, but the usefulness of this test is questionable and rarely alters the clinical management of the vitamin B12 deficiency. The Schilling test was once performed to determine whether replacement of vitamin B12 should occur via an oral or parenteral route, but evidence now shows that oral replacement is as efficacious as parenteral supplementation because of the vitamin B12absorption pathway independent of intrinsic factor.28,33


Vitamin B12 Deficiency Anemia

The goals of treatment for vitamin B12 deficiency include reversal of hematologic manifestations, replacement of body stores, and prevention or resolution of neurologic manifestations. Early treatment is of paramount importance because neurologic damage may be irreversible if the deficiency is not detected and corrected within months. In addition to replacement therapy, any underlying etiology that is treatable, such as bacterial overgrowth, should be remedied. Indications for starting oral or parenteral therapy include megaloblastic anemia or other hematologic abnormalities and neurologic disease from deficiency.30 Those with borderline low levels of B12 but no hematologic abnormalities should be followed at yearly intervals.30 Patients should be counseled on the types of foods high in vitamin B12 content such as fortified cereals as seen in Table 80–6. Orally administered vitamin B12 can be used effectively to treat pernicious anemia because of the aforementioned alternate pathway of passive absorption, independent of intrinsic factor.14 Daily oral doses (1,000 to 2,000 mcg) of vitamin B12 is as effective as intramuscular administration in achieving hematologic and neurologic responses.28,33 If vitamin B12levels are marginally low and either MMA or both MMA and homocysteine levels are elevated, administration of 1,000 mcg of oral vitamin B12daily should be strongly considered.34 Timed-release preparations of oral cobalamin should be avoided.35 Nonprescription 1,000 mcg cobalamin tablets are available, among several other strengths. A commonly used initial parenteral vitamin B12 regimen consists of daily injections of 1,000 mcg of cyanocobalamin for 1 week to saturate vitamin B12 stores in the body and resolve clinical manifestations of the deficiency. Thereafter, it can be given weekly for 1 month and monthly thereafter for maintenance. The series of daily parenteral injections may be omitted if administration is difficult or inconvenient. In this case the parenteral injection is then given weekly, sometimes for a longer than 1 month. Parenteral therapy is preferred for patients exhibiting neurologic symptoms until resolution of symptoms and normalization of hematologic indices because the most rapid-acting therapy is necessary.36When patients are converted from the parenteral to the oral form of cobalamin, 1,000 mcg of oral cobalamin daily can be initiated on the due date of the next injection. Vitamin B12 should be continued for life in pernicious anemia.

TABLE 80-6 Good Sources of Vitamin B 12


In addition to the oral and parenteral forms, vitamin B12 is available as a nasal spray for patients in remission following intramuscular vitamin B12 therapy who have no nervous system involvement. The nasal spray is administered once weekly. Intranasal administration should be avoided for patients with nasal diseases or those receiving medications intranasally in the same nostril. Patients should not administer the spray 1 hour before or after ingestion of hot foods or beverages, which can impair cobalamin absorption. The efficacy of the nasal spray formulation has not been well studied, and it should be used for maintenance therapy only after hematologic parameters have normalized.

Potential adverse effects with vitamin B12 replacement therapy are rare. Uncommon side effects include hyperuricemia and hypokalemia due to marked increase in potassium utilization during production of new hematopoietic cells.

Folic Acid Deficiency Anemia


Folic acid deficiency is one of the most common vitamin deficiencies occurring in the United States, largely because of its association with excessive alcohol intake and pregnancy.


Images Major causes of folic acid deficiency include inadequate intake, decreased absorption, and increased folate requirements. Poor eating habits make this deficiency more common for elderly patients, teenagers whose diets consist of “junk food,” alcoholics, food faddists, the impoverished, and those who are chronically ill or demented. Folic acid absorption may decrease for patients who have malabsorption syndromes or those who have received certain drugs. In alcoholics with poor dietary habits, alcohol interferes with folic acid absorption, interferes with folic acid utilization at the cellular level, and decreases hepatic stores of folic acid.

Increased folate requirements may occur when the rate of cellular division is increased, as seen in pregnant women; patients with hemolytic anemia, myelofibrosis, malignancy, chronic inflammatory disorders such as Crohn’s disease, rheumatoid arthritis, or psoriasis; patients undergoing long-term dialysis; burn patients; and for adolescents and infants during their growth spurts. This hyperutilization eventually can lead to anemia, particularly when the daily intake of folate is borderline, resulting in inadequate replacement of folate stores.

Several drugs have been reported to cause a folic acid deficiency megaloblastic anemia. Some drugs (e.g., azathioprine, 6-mercaptopurine, 5-fluorouracil, hydroxyurea, and zidovudine) directly inhibit DNA synthesis. Other drugs are folate antagonists; the most toxic is methotrexate (other examples include pentamidine, trimethoprim, and triamterene). A number of drugs (e.g., phenytoin, phenobarbital, and primidone) antagonize folate via poorly understood mechanisms but are thought to reduce vitamin absorption by the intestine (see eChap. 23). Since folic acid doses as low as 1 mg/day may affect serum phenytoin levels, routine folic acid supplementation is not generally recommended. The decline in phenytoin concentration usually occurs within the first 10 days and may decrease phenytoin levels by 15% to 50%.37


Folic acid is a water-soluble vitamin readily destroyed by cooking or processing. It is necessary for the production of DNA and RNA. It acts as a methyl donor to form methylcobalamin, which is used in the remethylation of homocysteine to methionine. Because humans are unable to synthesize sufficient folate to meet total daily requirements, they depend on dietary sources. Major dietary sources of folate include fresh, green leafy vegetables, citrus fruits, yeast, mushrooms, dairy products, and animal organs such as liver and kidney. Most folate in food is present in the polyglutamate form, which must be broken down into the monoglutamate form prior to absorption in the small intestine. Once absorbed, dietary folate must be converted to the active form tetrahydrofolate through a cobalamin-dependent reaction. In 1997, the United States mandated that grain products be fortified with folic acid in an attempt to increase the dietary intake of folate by 100 mcg of folate daily per person. This amount of supplementation was chosen to decrease the incidence of neural tube defects without masking occult vitamin B12 deficiency.

As a result of grain product fortification, neural tube defect frequency has decreased by 25% to 30%.38 Although body demands for folate are high because of high rates of RBC synthesis and turnover, the minimum daily requirement is 50 to 100 mcg. In the general population, the recommended daily allowance for folate is 400 mcg in nonpregnant females, 600 mcg for pregnant females, and 500 mcg for lactating females.38 Because the body stores about 5 to 10 mg of folate, primarily in the liver, cessation of dietary folate intake can result in deficiency within 3 to 4 months.

Laboratory Findings

It is of paramount importance to rule out vitamin B12 deficiency when folate deficiency is suspected. Laboratory changes associated with folate deficiency are similar to those seen in vitamin B12 deficiency, except vitamin B12 and MMA levels are normal. Serum folate levels decrease to less than 3 ng/mL (7 nmol/L) within a few days of reduced dietary folate intake. The RBC folate level (<150 ng/mL [<340 nmol/L]) also declines, and levels remain constant throughout the life span of the erythrocyte.12 If serum or erythrocyte folate levels are borderline, serum homocysteine usually is increased with a folic acid deficiency. If serum MMA levels also are elevated, vitamin B12 deficiency must be ruled out given that folate does not participate in MMA metabolism.


Folic Acid Deficiency Anemia

Therapy for folic acid deficiency consists of administration of exogenous folic acid to induce hematologic remission, replace body stores, and resolve signs and symptoms. In most cases, 1 mg daily is sufficient to replace stores, except in cases of deficiency due to malabsorption, in which case doses of 1 to 5 mg daily may be necessary. Parenteral folic acid is available but rarely necessary. Synthetic folic acid is almost completely absorbed by the GI tract and is converted to tetrahydrofolate without cobalamin. Therapy should continue for about 4 months if the underlying cause of the deficiency can be identified and corrected to allow for clearance of all folate-deficient RBCs from the circulation. Foods high in folic acid should also be encouraged in the diet as seen in Table 80–7. Long-term folate administration may be necessary in chronic conditions associated with increased folate requirements. Low-dose folate therapy (500 mcg daily) can be administered when anticonvulsant drugs produce a megaloblastic anemia so that discontinuation of anticonvulsant therapy may not be necessary. Adverse effects have not been reported with folic acid doses used for replacement therapy. It is considered nontoxic at high doses and is rapidly excreted in the urine.

TABLE 80-7 Good Sources of Folate


Although megaloblastic anemia during pregnancy is rare, the most common cause is folate deficiency. The condition usually manifests as an underweight premature infant and suboptimal health of the mother. Periconceptional folic acid supplementation is recommended to decrease the occurrence and recurrence of neural tube defects, specifically anencephaly and spinal bifida. Folic acid supplementation at a dose of 400 mcg daily is recommended for all women. Women who have previously given birth to offspring with neural tube defects or those with a family history of neural tube defects should ingest 4 mg daily of folic acid.3739 Higher levels of folic acid supplementation should not be attained via ingestion of excess multivitamins because of the risk for fat soluble vitamin toxicity.39 Prenatal vitamins usually have a higher amount of folic acid as compared with general multivitamins to ensure adequate supplementation is attained. It is essential that women in their childbearing years maintain adequate folic acid intake.



Images AI is a newer term used to describe both ACD and anemia of critical illness. This new term was developed to reflect the inflammatory process that underlies both of those types of anemia. The onset of anemia of critical illness is quicker, over days, and typically occurs in a hospital setting. ACD has a similar mechanism, but it develops over months to years from a chronic condition. AI is one of the most common forms of anemia seen clinically, particularly among the elderly. It is especially important in the differential diagnosis of iron deficiency. ACD is associated with common disease states that may mimic the symptoms of anemia, which causes the diagnosis of ACD to sometimes be overlooked in the outpatient setting. Anemia of critical illness is a common complication in critically ill patients and is found almost universally in this patient population.40 About 95% of patients have less than normal Hb levels by their third day in the intensive care unit.41


The diagnosis of AI usually is one of exclusion. It is important to exclude IDA as the true or competing etiology. Various conditions associated with ACD may predispose patients to blood loss (malignancy, GI blood loss from treatments with aspirin, NSAIDs, or corticosteroids). ACD is often observed in patients with diseases that last longer than 1 to 2 months, although it can occur in conditions with a more rapid onset of several weeks, such as pneumonia. ACD tends to be a mild (Hb >9.5 g/dL [>95 g/L; >5.90 mmol/L]) or moderate (Hb >8 g/dL [80 g/L; >4.97 mmol/L]) anemia.42 Anemia associated with human immunodeficiency virus (HIV), autoimmune conditions, cancer, and heart failure are common forms of ACD. The degree of anemia in ACD is generally reflects the severity of underlying disease. Table 80–8 lists common diseases associated with ACD.

TABLE 80-8 Diseases Causing Anemia of Inflammation


Factors that may contribute to anemia in critically ill patients include sepsis, frequent blood sampling, surgical blood loss, immune-mediated functional iron deficiency, decreased production of endogenous EPO, reduced RBC life span, and active bleeding, especially in the GI tract. More commonly, a combination of these factors exists. This combination creates an anemic state over days. Additional comorbid factors include coagulopathies and nutritional deficits such as poor oral intake and altered absorption of vitamins and minerals, including iron, vitamin B12, and folate.43 Deleterious effects of anemia include an increased risk of cardiac-related morbidity and mortality, especially for patients with known cardiovascular disease. Persistent tissue hypoxia can result in cerebral ischemia, myocardial ischemia, multiple organ deterioration, lactic acidosis, and death. Consequences of anemia in critically ill patients may be enhanced because of the increased metabolic demands of critical illness. Weaning anemic patients from mechanical ventilation may be more difficult.44


AI is a response to stimulation of the cellular immune system by various underlying disease processes. AI is a hypoproliferative anemia that traditionally has been associated with infectious or inflammatory processes, tissue injury, and conditions associated with release of proinflammatory cytokines. The pathogenesis of AI is multifactorial and is characterized by a blunted EPO response to anemia, an impaired proliferation of erythroid progenitor cells, and a disturbance of iron homeostasis. Increased iron uptake and retention occur within cells. The RBCs have a shortened life span, and the bone marrow’s capacity to respond to EPO is inadequate to maintain normal Hb concentration. The cause of this defect is uncertain but appears to involve blocked release of iron from cells in the bone marrow. Iron availability to erythroid progenitor cells then is limited. Various cytokines, such as interleukin-1, interferon-γ, interlukin-6, and tumor necrosis factor released during illness may inhibit the production or action of EPO or the production of RBCs.42 These cytokines also upregulate hepcidin, which blocks iron release from storage cells.45Hepicidin also decreases duodenal absorption of iron.42

Laboratory Findings

No definitive test can confirm the diagnosis of AI. The practitioner should maintain a high index of suspicion for any patient with a chronic inflammatory or neoplastic disease. AI may coexist with IDA and folic acid deficiency because many patients with these conditions have poor dietary intake or GI blood loss. Examination of the bone marrow reveals an abundance of iron, suggesting that the release mechanism for iron is the central defect. Patients with AI usually have a decreased serum iron level, but unlike patients with IDA, their serum ferritin level is normal or increased and their TIBC is decreased. Transferrin saturation is typically decreased. AI usually is normocytic and normochromic with mildly depressed Hb. Patients with concurrent AI and IDA usually have microcytes and a more severe anemia. Table 80–9 shows lab values seen in AI and IDA. Erythrocyte survival may be reduced for patients with AI, but a compensatory erythropoietic response does not occur. A low reticulocyte count indicates underproduction of RBCs.42

TABLE 80-9 Laboratory Value Differences Between Anemia of Inflammation and Iron-Deficiency Anemia



Anemia of Inflammation

Treatment of AI depends somewhat on the underlying etiology. Guidelines exist for management of anemia for patients with cancer or chronic kidney disease (see Chaps. 29 and 104). Although the goals of therapy should include treating the underlying disorder and correcting reversible causes of anemia, accomplishment of these goals may not totally reverse hematologic and physiologic abnormalities. Iron is effective only if iron deficiency is present. During inflammation, oral or parenteral iron therapy is not as effective. Absorption is impaired because of downregulation of ferroportin and iron diversion mediated by cytokines.42 Because iron is a required nutrient for proliferating microorganisms, supplementation may theoretically increase the risk of infections. Iron therapy should be reserved for those patients with an established iron deficiency.42

Clinical Controversy…

The low iron concentrations in critically ill patients may be a defense mechanism, as microbes require iron for sustenance. Therefore, diminished iron levels may inhibit bacterial growth. Further investigation of the net benefit of supplementation with iron is warranted.

RBC transfusions are effective but should be limited to situations in which oxygen transport is inadequate due to concomitant medical problems. Transfusions are typically considered for those with severe anemia (Hb <7 to 8 g/dL [<80 g/L; <4.97 mmol/L]) but can be considered for those between 8 and 10 g/dL (80 to 100 g/L; 4.97 to 6.21 g/L) based on factors such as cost, convenience, and risk of complications. Transfusion risks may include transmission of bloodborne infections, development of autoantibodies, transfusion reactions, and iron overload.

ESAs have been used to stimulate erythropoiesis for patients with AI since a relative EPO deficiency exists for the degree of anemia. Two agents are available: recombinant epoetin alfa and recombinant darbepoetin alfa. Although both agents share the same mechanism of action, darbepoetin alfa has a longer half-life and can be administered less frequently. Although these agents are sometimes used to treat AI, they are not FDA-approved for this indication. Patients with chronic disease may have a relatively impaired response to ESAs. The initial dosage of epoetin alfa and darbepoetin alfa are typically 50 to 100 units per kilogram three times per week and 0.45 mcg per kilogram once weekly, respectively. These doses are typical starting doses for those with chronic kidney disease. Response to ESAs varies depending on dose and cause of the anemia. ESA treatment is effective when the marrow has an adequate supply of iron, cobalamin, and folic acid.

Iron deficiency can occur in patients treated with ESAs; so close monitoring of iron levels is necessary. Some patients develop “functional” iron deficiency, in which the iron stores are normal but the supply of iron to the erythroid marrow is less than necessary to support the demand for RBC production. Therefore, many practitioners routinely supplement ESA therapy with oral iron therapy. Potential toxicities of exogenous ESA administration include increases in blood pressure, nausea, headache, fever, bone pain, and fatigue. Less common adverse effects include seizures, thrombotic events, and allergic reactions such as rashes and local reactions at the injection site. If ESAs are used the practitioner must monitor to ensure the patient’s Hb does not exceed 12 g/dL (120 g/L; 7.45 mmol/L) with treatment or that Hb does not rise >1 g/dL (>10 g/L; >0.62 mmol/L) every 2 weeks since both of these events have been associated with increased mortality and cardiovascular events.46 Tumor progression with these agents can also occur and is discussed in Chapter 104. Further discussion of dosing guidelines and potential adverse outcomes of ESA treatment in populations for which treatment is FDA approved are discussed in Chapters 29 and 104.

Patients who are critically ill require the necessary substrates of iron, folic acid, and vitamin B12 for RBC production. Parenteral iron is generally preferred in this population because patients often are undergoing enteral therapy or because of concerns regarding inadequate iron absorption. The disadvantage of parenteral therapy is the theoretical risk of infection.

Pharmacologic doses of ESAs have been used to treat the anemia of critical illness. Few randomized controlled trials have evaluated the role of ESAs in critically ill patients, and the results of these trials have not consistently shown a decrease in transfusion requirements in ESA-treated patients.47 Further investigation is necessary to determine the effectiveness of ESAs in critically ill patients.41 These agents are not FDA approved in this setting.

Many critically ill patients receive RBC transfusions despite the inherent risks associated with transfusions. Stored RBCs may not function as well as endogenous blood. Although RBC transfusions may increase oxygen delivery to tissues, cellular oxygen may not increase.48 Transfusion practices in ICUs vary, and clinicians use different Hb concentrations as thresholds for administering transfusions. The decision to use transfusions must consider the risks, including transmission of infections; volume overload, especially for patients with renal or heart failure; iron overload; and immune-mediated reactions such as febrile reactions, hemolysis, and anaphylaxis. The clinician also must consider administrative, logistic, and economic factors, including the shortage of blood supplies.



Images One of the most common clinical problems observed in the elderly is anemia. Anemia is a prevalent and increasing problem in the elderly, with about 20% of people 85 years and older affected.49 Elderly patients with the highest incidence of anemia are those who are hospitalized, followed by residents of nursing homes and other institutions, with an estimated rate of 31% to 40%.50 Although the incidence of anemia is high in the elderly, anemia should not be regarded as an inevitable outcome of aging. The body’s set point of Hb does not fall with age. An underlying cause can be identified in about two thirds of older patients. Undiagnosed and untreated anemia has been associated with adverse outcomes, including all-cause hospitalization, hospitalization secondary to cardiovascular disease, and all-cause mortality.51Anemia is an independent predictor of death and major clinical adverse events in elderly patients with stable symptomatic coronary artery disease.52 Anemia can exacerbate neurologic and cognitive conditions and can adversely influence quality of life and physical performance in the elderly.53 Anemia may be an indication of serious diseases such as GI cancer.


Aging is associated with a progressive reduction in hematopoietic reserve, which makes individuals more susceptible to developing anemia in times of hematopoietic stress.54 Dysregulation of proinflammatory cytokines, most notably interleukin-6, may inhibit EPO production or interact with EPO receptors.55 Although Hb levels may remain normal, the diminished marrow reserve leaves the elderly patient more susceptible to other causes of anemia. Renal insufficiency, which also is common in elderly patients, may reduce the ability of the kidneys to produce EPO. Older patients often have a normal creatinine level but a diminished glomerular filtration rate. Myelodysplastic syndromes are another common cause of anemia in the elderly, but most anemia cases in the elderly are multifactorial.


In the acute care setting, the top three causes of anemia in the elderly are chronic disease (35%), unexplained cause (17%), and iron deficiency (15%), whereas in community-based outpatient clinics, the most common causes are unexplained (36%), infection (23%), and chronic disease (17%).56

Another common problem in the elderly is vitamin B12 deficiency. The most common causes of clinically overt vitamin B12 deficiency are food/cobalamin malabsorption (more than 60% of cases) and pernicious anemia (15% to 20% of cases).57

One often-overlooked major factor that may contribute to anemia in the older population is nutritional status. Cognitive and functional impairments in the older population may create barriers for patients to obtain and prepare a nutritious diet. Nutritional deficiencies that are not severe enough to affect the hematopoietic system in the younger population may contribute to anemia in the elderly. Edentulous or infirm elderly who may be too ill to prepare their meals are at risk for nutritional folate deficiency. Risk factors for inadequate folate intake in the elderly include low caloric intake, inadequate consumption of fortified cereals, and failure to take a vitamin/mineral supplement. However, unlike cobalamin levels, folate levels often increase rather than decline with age. High folic acid intake can occur if the elderly patient regularly uses a supplement and consumes fortified cereals.58,59

Bleeding with resultant iron deficiency in the elderly may be due to carcinoma, peptic ulcer, atrophic gastritis, drug-induced gastritis, postmenopausal vaginal bleeding, or bleeding hemorrhoids. Elderly women have a much lower incidence of IDA compared with younger, menstruating women. Until proven otherwise, iron deficiency in the elderly should be considered a sign of chronic blood loss. Steps should be taken to rule out bleeding, especially from the GI or female reproductive tract. AI is more common in the elderly, as diseases that contribute to AI such as cancer, infection, and rheumatoid arthritis are more prevalent in this population.

Laboratory Findings

For practical purposes, it is best to use usual adult reference values and WHO criteria for laboratory tests in the elderly. Anemia in elderly persons usually is normocytic and mild, with Hb values ranging between 10 and 12 g/dL (100 to 120 g/L; 6.21 to 7.45 mmol/L) in most anemic patients.49 Evaluation of an elderly patient should be similar to strategies described previously for younger adults, perhaps with more emphasis on identifying occult blood loss and vitamin B12 deficiency. Vitamin B12 deficiency may be present even when plasma levels of vitamin B12 are within the normal range, but elevated MMA levels will reveal the deficiency. A refractory macrocytic anemia in the elderly should raise suspicion of a myelodysplastic syndrome.


Anemia in the Elderly

Treatment of anemia in the elderly is the same as that described for each type of anemia discussed in this chapter. With IDA it is essential to treat the underlying cause, if known (i.e., bleeding), and administer iron supplementation. Lower doses of iron supplementation are often recommended in the elderly (e.g., 325 mg of ferrous sulfate once daily) to decrease the incidence of GI adverse effects, which can lead to additional morbidity and poor adherence. The goal of treatment of AI is resolution of the underlying cause, although curing the underlying chronic illness for elderly patients can be difficult. Routine treatment with ESAs is not currently standard of care for AI in the elderly.



Images IDA is a leading cause of infant morbidity and mortality around the world.60 Data from NHANES III indicated that 9% of children ages 12 to 36 months in the United States had iron deficiency and 3% had IDA.61,62 Lack of a normal Hb at birth directly affects nonstorage iron and increases the risk of IDA in the first 3 to 6 months of life. African American or Hispanic-American children have a higher incidence of anemia.63 Requirements for iron absorption peak during puberty. An anemia of prematurity can occur 3 to 12 weeks after birth in infants younger than 32 weeks’ gestation and spontaneously resolves by 3 to 6 months. The prevalence of vitamin B12 deficiency has been identified as 1 in 1,255 for levels <100 pg/mL (<74 pmol/L) and 1 in 200 for levels of <200 pg/mL (<148 pmol/L), with the lowest levels in non-Hispanic whites.64


In contrast to anemias in adults, which tend to be manifestations of a broader underlying pathology, anemias in the pediatric population are more often due to a primary hematologic abnormality. The amount of iron present at birth depends on gestational length and weight. A decrease in EPO production results in a physiologic anemia peaking at 2 months.65 Iron stores from birth are mostly depleted by 6 months of age.


The age of the child can yield some clues regarding the etiology of the anemia. The optimal amount of nutritional iron and folate required varies among individuals based on life-cycle stages. Two peak periods place children at risk of developing IDA. The first peak period occurs during late infancy and early childhood, when children undergo rapid body growth, have low levels of dietary iron, and exhaust stores accumulated during gestation. The second peak period occurs during adolescence, which is associated with rapid growth, poor diets, and onset of menses in girls. Some studies suggest that overweight children are at significantly higher risk for IDA. Proposed factors include genetic influences; physical inactivity, leading to decreased myoglobin breakdown and lower amounts of released iron into the blood; and inadequate diet with limited intake of iron-rich foods.66

Conditions in the newborn period that can lead to IDA include prematurity and insufficient dietary intake. Premature infants are at increased risk for IDA because of their smaller total blood volume, increased blood loss through phlebotomy, and poor GI absorption. Factors leading to unbalanced iron metabolism in infants include insufficient iron intake, early introduction of cow’s milk, intolerance of cow’s milk, medications, and malabsorption. Dietary deficiency of iron in the first 6 to 12 months of life is less common today because of the increased use of iron supplementation during breast-feeding and use of iron-fortified formulas. Iron deficiency becomes more common when children change to regular diets.

When screening for iron deficiency in young children, a careful dietary history can help identify children at risk. High iron needs and the tendency to eat fewer iron-containing foods contribute to the etiology of iron deficiency during adolescence.

Other causes of microcytic anemia include thalassemia, lead poisoning, and sideroblastic anemia. Use of homeopathic or herbal medications and exposure to paint or certain cooking materials may place children at risk for lead exposure. Normocytic anemias in children include infection with human parvovirus B19 and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Macrocytic anemias are caused by deficiencies in vitamin B12 and folate, chronic liver disease, hypothyroidism, and myelodysplastic disorders. Folic acid deficiency usually is due to inadequate dietary intake, but human milk and cow’s milk provide adequate sources. Folic acid deficiency may be seen in infants and children who primarily consume goat’s milk or health food milk alternatives, or in children with insufficient intake of green leafy vegetables. Vitamin B12 deficiency due to nutritional reasons is rare but may occur due to a congenital pernicious anemia.

Laboratory Findings

When evaluating laboratory values for pediatric patients, the clinician must use age- and sex-adjusted norms. It is important to know that many blood samples are capillary samples, such as heel or finger sticks, which may have slightly different results than venous samples. The USPSTF has concluded that evidence is insufficient to recommend for or against routine screening for IDA in asymptomatic, low risk, children aged 6 to 12 months. The Hb is a sensitive test for iron deficiency, but it has low specificity in childhood anemias. If an abnormality is found, a CBC should be ordered to evaluate MCV and determine whether the anemia is microcytic, normocytic, or macrocytic. A peripheral blood smear and reticulocyte count also may be helpful. The peripheral blood smear can indicate the etiology based on RBC morphology, and the reticulocyte count helps differentiate between decreased RBC production and increased RBC destruction or loss. Other laboratory tests include serum iron, ferritin, TIBC, and transferrin saturation. Mild hereditary anemias may produce a mild hypochromic microcytic anemia that can be confused with IDAs. The RDW may be high with iron deficiency and is more likely to be normal with thalassemia. Laboratory features of anemia of prematurity include normocytic normochromic cells, low reticulocyte count, low serum EPO concentrations, and decreased RBC precursors in bone marrow. Laboratory diagnosis of vitamin B12 and folate deficiency in children is similar to that of adults.


Anemia in Pediatric Populations

Primary prevention of IDA in infants, children, and adolescents is the most appropriate goal because delays in mental and motor development are potentially irreversible. In 2006, the USPSTF published revised recommendations to screen and supplement iron deficiency in the United States, focusing on children and pregnant women.17 The USPSTF recommends routine iron supplementation for asymptomatic children aged 6 to 12 months who are at increased risk for IDA. Fair evidence was found that iron supplementation (e.g., iron-fortified formula or iron supplements) might improve neurodevelopmental outcomes in children at risk for IDA. The quality of evidence of benefit for children 6 to 12 months of age not at risk for IDA was poor.

Interventions likely to prevent anemia include diverse foods with bioavailable forms of iron, food fortification for infants and children, and individual supplementation. Routine screening for iron deficiency in nonpregnant adolescents is recommended only for those with risk factors, which include vegetarian diets, malnutrition, low body weight, chronic illness, or history of heavy menstrual blood loss.

Anemia of prematurity is frequently treated with RBC transfusions, with wide variations in transfusion practices among neonatal ICUs. Reasons for transfusions include improved oxygen delivery, increased intravascular volume, reduced fatigue during feeding, and improved growth. ESAs have been used to treat anemia of prematurity, but it is important to note that ESA pharmacokinetics differ depending on the developmental age of the infant. ESA use is controversial because it has not been shown to clearly reduce transfusion requirements. Other questions regarding safety and proper use of ESAs in anemia of prematurity remain unanswered.

For infants aged 9 to 12 months with a mild microcytic anemia, the most cost-effective treatment is a therapeutic trial of iron. Fe2+ sulfate at a dose of 3–6 mg/kg/day of elemental iron divided once or twice daily between meals for 4 weeks is recommended. In children who respond, iron should be continued for two more months to replace storage iron pools, along with dietary intervention and patient education.67Parenteral iron therapy has a limited role and is rarely necessary.

For the macrocytic anemias in children, folate can be administered in a dose of 1 mg daily. However, vitamin B12 deficiency due to congenital pernicious anemia requires lifelong vitamin B12 supplementation. Dose and frequency should be titrated according to clinical response and laboratory values. No data regarding the use of oral vitamin B12 supplementation in children are available.


In the treatment of the anemias discussed in this chapter, personalized pharmacotherapy is important in a few populations. When treating IDA, the elderly should be treated with lower doses of oral iron therapy. This typically is once daily dosing with ferrous sulfate 325 mg. Patients with immune-mediated disease are at higher risk for having hypersensitivity reactions to parenteral iron therapy. Patients who have neurologic symptoms upon diagnosis of vitamin B12 deficiency should strongly be considered for parenteral B12 supplementation. If ESAs are used to treat AI, iron status should be closely monitored to ensure efficacy of these agents as functional iron deficiency can develop.


For IDA, a positive response to a trial of oral iron therapy is characterized by a modest reticulocytosis in days, with an increase in Hb starting after about 2 weeks with continued rapid rise in Hb. As the Hb level approaches normal, the rate of increase slows progressively. Hb should reach a normal level after about 2 months of therapy and often sooner.9 If the patient does not develop reticulocytosis, reevaluation of the diagnosis or iron replacement therapy is necessary. Iron therapy should continue for a period sufficient for complete restoration of iron stores. Serum ferritin concentrations should return to the normal range prior to discontinuation of iron. The time interval required to accomplish this goal varies, although at least 6 to 12 months of therapy usually is warranted. Patients with negative iron balances caused by bleeding may require iron replacement therapy for only 1 month after correction of the underlying lesion, whereas patients with recurrent negative balances may require long-term treatment with as little as 30 to 60 mg of elemental iron daily.

When large amounts of parenteral iron are administered, by either total dose infusion or multiple intramuscular or IV doses, the patient’s iron status should be closely monitored. Patients receiving regular IV iron should be monitored for clinical or laboratory evidence of iron toxicity or overload. Iron overload may be indicated by abnormal hepatic function tests, serum ferritin >800 ng/mL (>800 g/L), or transferrin saturation >50%. Serum ferritin and transferrin saturation should be measured in the first week after larger IV iron doses. Hb and Hct should be measured weekly, and serum iron and ferritin levels should be measured at least monthly.

In the treatment of vitamin B12 deficiency anemia, most patients respond rapidly to vitamin B12 therapy. The typical patient will experience an improvement in strength and well-being within a few days of treatment initiation. Reticulocytosis is evident in 3 to 5 days. Hb begins to rise after the first week and should normalize in 1 to 2 months. CBC count and serum cobalamin levels usually are drawn 1 to 2 months after initiation of therapy and 3 to 6 months thereafter for surveillance monitoring. Homocysteine and MMA levels can be repeated 2 to 3 months after initiation of replacement therapy to evaluate for normalization of levels, although levels begin to decrease in 1 to 2 weeks. Neuropsychiatric signs and symptoms can be reversible if treated early. If permanent neurologic damage has resulted, progression should cease with replacement therapy. Slow response to therapy or failure to observe normalization of laboratory results may suggest the presence of an additional abnormality such as iron deficiency, thalassemia trait, infection, malignancy, nonadherence, or misdiagnosis.

In folic acid deficiency anemia, symptomatic improvement, as evidenced by increased alertness and appetite, often occurs early during the course of treatment. Reticulocytosis begins in the first week. Hct begins to rise within 2 weeks and should reach normal levels within 2 months. MCV initially increases because of an increase in reticulocytes but gradually decreases to normal.

When using ESAs, one of the earliest responses is an increase in blood reticulocyte count, which usually occurs in the first few days. Baseline iron status should be checked before and during treatment, as many patients receiving ESAs require supplemental iron therapy. The optimal form and schedule of iron supplementation are not known. Hb levels should be monitored twice a week until stabilized. Hb should also be monitored twice weekly for 2 to 6 weeks after a dose adjustment.46 A fall in Hb during ESA therapy may indicate a need for iron supplementation or signal occult blood loss. Baseline and periodic monitoring of iron, TIBC, transferrin saturation, or ferritin levels may be useful in optimizing iron repletion and limiting the need for ESAs. Patients who do not respond to 8 weeks of optimal dosage should not continue taking ESAs. Target Hb levels should be 11 to 12 g/dL (110 to 120 g/L; 6.83 to 7.45 mmol/L). Cost is an issue with ESA therapy; therefore, drug cost must be weighed against the effects on transfusions and hospitalizations.

Responses and monitoring of treatment are similar in the elderly as described for the general adult population described earlier in the chapter. If the reticulocyte count rises but the anemia does not improve, inadequate absorption of iron or continued blood loss should be suspected. As with any form of anemia, symptomatic improvement should be evident shortly after starting therapy, and Hb/Hct should begin to rise within a few weeks of initiating therapy. A key component of symptom assessment among older adults is the functional domain. Patients should be asked about changes in self-care abilities, mobility, and stamina.

Therapeutic outcomes are assessed in children by monitoring Hb, Hct, and RBC indices 4 to 8 weeks after initiation of iron therapy. For premature infants, Hb or Hct should be monitored weekly.




    1. Benoist B, McLean E, Egli M, et al. Worldwide prevalence of anaemia 1993–2005: WHO global database on anaemia. World Health Organization; 2008.

    2. Cusick SE, Mei Z, Freedman DS, et al. Unexplained decline in the prevalence of anemia among US children and women between 1988–1994 and 1999–2002. Am J Clin Nutr 2008;88:1611–1617.

    3. Nissenson A. Anemia not just an innocent bystander. Arch Intern Med 2003;163:1400–1404.

    4. Mozaffarian D. Anemia predicts mortality in severe heart failure: The prospective randomized amlodipine survival evaluation (PRAISE). J Am Coll Cardiol 2003;41:1933–1939.

    5. Chaves PHM, Carlson MC, Ferrucci L, et al. Association between mild anemia and executive function impairment in community-dwelling older women: The Women’s Health and Aging Study II. J Am Geriatr Soc 2006;54:1429–1435.

    6. Anemia in pregnancy. ACOG Practice Bulletin No. 95. American College of Obst and Gynecologists. Obstet Gynecol 2008;112:201–207.

    7. Prchal JT. Production of erythrocytes. In: Kaushansky K, Lichtman MA, Beutler E, et al, eds. Williams Hematology, 8th ed. New York: McGraw-Hill; 2010:453–448.

    8. Wians FH, Urban JE, Keffer JH, Kroft SH. Discriminating between iron deficiency anemia and anemia of chronic disease using traditional indices of iron status vs. transferrin receptor concentration. Am J Clin Pathol 2001;115:112–118.

    9. Beutler E. Disorders of iron metabolism. In: Kaushansky K, Lichtman MA, Beutler E, et al, eds. Williams Hematology, 8th ed. New York: McGraw-Hill; 2010:565–606.

   10. Beutler E. Destruction of erythrocytes. In: Kaushansky K, Lichtman MA, Beutler E, et al., eds. Williams Hematology, 8th ed. New York: McGraw-Hill; 2010:449–454.

   11. Galloway M, Rushworth L. Red cell or serum folate? Results from the National Pathology Alliance benchmarking review. J Clin Pathol 2003;56:924–926.

   12. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency. Arch Intern Med 1999;159:1289–1298.

   13. Green R. Folate, cobalamin, and megaloblastic anemias. In: Kaushansky K, Lichtman MA, Beutler E, et al., eds. Williams Hematology, 8th ed. New York: McGraw-Hill; 2010:533–564.

   14. Dharmarajan TS, Norkus EP. Approaches to vitamin B12 deficiency. Early treatment may prevent devastating complications. Postgrad Med 2001;110:99–105.

   15. Ganz T. Hepcidin—A regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract Res Clin Haematol 2005;18:171–182.

   16. Goodnough LT, Nemeth E, Gan T. Detection, evaluation, and management of iron restricted erythropoiesis. Blood 2010;116:4754–4761.

   17. Killip S, Bennett J, Chambers M. Iron deficiency anemia. Am Fam Physician 2007;75:671–678.

   18. Hershko C, Ianculovich M, Souroujon M. A hematologist’s view of unexplained iron deficiency anemia in males: Impact of Helicobacter pylori eradication. Blood Cells Mol Dis 2007;38:45–53.

   19. U.S. Preventive Services Task Force (USPSTF). Screening for Iron Deficiency Anemia—Including Iron Supplementation for Children and Pregnant Women. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2006.

   20. Faich G, Strobos J. Sodium Fe3+ gluconate complex in sucrose: Safer IV iron therapy than iron dextrans. Am J Kidney Dis 1999;33:464–470.

   21. Chandler G, Harchowal J, Macdougall IC. Intravenous iron sucrose: Establishing a safe dose. Am J Kidney Dis 2001;38:988–991.

   22. Silverstein SB, Gilreath JA, Rodgers GM. Intravenous iron therapy: A summary of treatment options and review of guidelines. J Pharm Practice 2008;21:431–443.

   23. InFeD [package insert]. Morristown, NJ: Watson Pharma; 2009.

   24. Munoz M, Garcia-Erce JA, Remacha AF. Disorders of iron metabolism: Part II: Iron deficiency and iron overload. J Clin Pathol 2011;64:287–296.

   25. Ferrlecit [package insert]. Morristown, NJ: Watson Pharma; 2006.

   26. Venofer [package insert]. Shirley, NY: American Regent; 2008.

   27. Feraheme [package insert]. Lexington, MA: AMAG Pharmaceuticals; 2009.

   28. Oh RC, Brown DL. Vitamin B12 deficiency. Am Fam Physician 2003;67:979–986, 993–994.

   29. Kaptan K, Beyan C, Ural AU, et al. Helicobacter pylori—Is it a novel causative agent in vitamin B12 deficiency? Arch Intern Med 2000;160:1349–1353.

   30. Hoffbrand AV. Chapter 105. Megaloblastic Anemias. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine, 18th ed. New York: McGraw-Hill; 2012.

   31. Aronow WS. Homocysteine. The association with atherosclerotic vascular disease in older persons. Geriatrics 2003;58:22–28.

   32. Green R. Indicators for assessing folate and vitamin b-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr 2011;94(Suppl):666S–672S.

   33. Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev 2005;3:CD004655.

   34. Cravens DD, Nashelsky J, Oh RC. How do we evaluate a marginally low B12 level? J Fam Pract 2007;56:62–63.

   35. Solomon LR. Oral vitamin B12 therapy: A cautionary note. Blood 2004;103:2863.

   36. Lane LA, Rojas-Fernandez. Treatment of vitamin B12-deficiency anemia: Oral versus parenteral therapy. Ann Pharmacother 2002;36:1268–1272.

   37. Yerby MS. Clinical care of pregnant women with epilepsy: Neural tube defects and folic acid supplementation. Epilepsia 2003;44(Suppl 3):33–40.

   38. Pitkin RM. Folate and neural tube defects. Am J Clin Nutr 2007;85:285S–288S.

   39. American College of Obstetricians and Gynecologists (ACOG). Neural Tube Defects. ACOG Practice Bulletin No. 44. Washington, DC: American College of Obstetricians and Gynecologists, 2003.

   40. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: Anemia and blood transfusion in the critically ill—Current clinical practice in the United States. Crit Care Med 2004;32:39–52.

   41. Stubbs JR. Alternatives to blood product transfusion in the critically ill: Erythropoietin. Crit Care Med 2006;34(Suppl):S160–S169.

   42. Weiss GW, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352:1011–1023.

   43. Rodriguez RM, Corwin HL, Gettinger A, et al. Nutritional deficiencies and blunted erythropoietin response as cause of anemia of critical illness. J Crit Care 2001;16:36.

   44. Silver MR. Anemia in the long-term ventilator-dependent patient with respiratory failure. Chest 2005;128(Suppl):568S–575S.

   45. Adamson J. The anemia of inflammation/malignancy: Mechanisms and management. Hematology Am Soc Hematol Educ Program 2008;159–165.

   46. Procrit [package insert]. Thousand Oaks, CA: Amgen, 2009.

   47. Rudis M, Jacobi J, Hassan E, et al. Managing anemia in the critically ill patient. Pharmacotherapy 2004;24:229–247.

   48. Hébert PC, Wells G, Martin C, et al. Do blood transfusions improve outcomes related to mechanical ventilation? Chest 2001;119:1850–1857.

   49. Guralnik JM, Eisenstaedt RS, Ferrucci L, et al. Prevalence of anemia in person 65 years and older in the United States: Evidence for a high rate of unexplained anemia. Blood 2004;104:2263–2268.

   50. Carmel R. Anemia and aging: An overview of clinical, diagnostic, and biological issues. Blood Rev 2001;15:9–18.

   51. Culleton BF, Manns BJ, Zhang J, et al. Impact of anemia on hospitalization and mortality in older adults. Blood 2006;107:3841–3846.

   52. Muzzarelli S, Pfisterer M, TIME Investigators. Anemia as independent predictor of major events in elderly patients with chronic angina. Am Heart J 2006;152:991–996.

   53. Woodman R, Ferrucci L, Guralnik J. Anemia in older adults. Curr Opin Hematol 2005;12:123–128.

   54. Balducci L, Hardy CL, Lyman GH. Hematopoietic growth factors in the older cancer patient. Curr Opin Hematol 2001;8:170–187.

   55. Eisenstaedt R, Penninx BW, Woodman RC. Anemia in the elderly: Current understanding and emerging concepts. Blood Rev 2006;20:213–226.

   56. Balducci L. Epidemiology of anemia in the elderly: Information on diagnostic evaluation. J Am Geriatr Soc 2003;51(Suppl):S2–S9.

   57. Andres E, Loukili N, Noel E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 2004;171:251–259.

   58. Mulligan JE, Greene GW, Caldwell M. Sources of folate and serum folate levels in older adults. J Am Diet Assoc 2007;107:495–499.

   59. Ford ES, Bowman BA. Serum and red blood cell folate concentrations, race, and education: Findings from the third National Health and Nutrition Examination Survey. Am J Clin Nutr 1999;69:476–481.

   60. Milman N. Iron prophylaxis in pregnancy—General or individual and in which dose? Ann Hematol 2006;85:821–828.

   61. Recommendations to prevent and control iron deficiency in the United States. Morb Mortal Wkly Rep 1998;47:1–36.

   62. Moy RJ. Prevalence, consequences and prevention of childhood nutritional iron. Clin Lab Haematol 2006;28:291–298.

   63. Coyer S. Anemia: Diagnosis and management. J Pediatr Health Care 2005;19:380–385.

   64. Wright JD, Bialostosky K, Gunter EW, et al. Blood folate and vitamin B12: United States, 1988–94. Vital Health Stat 1998;11:1–78.

   65. Palis J, Segel GB. Chapter 6. Hematology of the Fetus and Newborn. In: Prchal JT, Kaushansky K, Lichtman MA, Kipps TJ, Seligsohn U, eds. Williams Hematology. 8th ed. New York: McGraw-Hill, 2010.

   66. Nead KG, Halterman JS, Kaczorowski JM, et al. Overweight children and adolescents: A risk group for iron deficiency. Pediatrics 2004;114:104–108.

   67. Kazal LA. Prevention of iron deficiency in infants and toddlers. Am Fam Physician 2002;66:1217–1224.