AnemiaMarcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama

Updated: Dec 2, 2009

IntroductionBackground

Microcytic anemia.

Peripheral smear showing ovalocytes, macrocytes, and a hypersegmented polymorphonuclear leukocyte.

Anemia, like a fever, is a symptom of disease that requires investigation to determine the underlying etiology. Often, practicing physicians overlook mild anemia. This is similar to failing to seek the etiology of a fever. The purpose of this article is to provide a method of determining the etiology of an anemia.

Anemia is strictly defined as a decrease in red blood cell (RBC) mass. Methods for measuring RBC mass are time consuming, are expensive, and usually require transfusion of radiolabeled erythrocytes. Thus, in practice, anemia is usually discovered and quantified by measurement of the RBC count, hemoglobin (Hb) concentration, and hematocrit (Hct). These values should be interpreted cautiously because they are concentrations affected by changes in plasma volume. For example, dehydration elevates these values, and increased plasma volume in pregnancy can diminish them without affecting the RBC mass.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

Pathophysiology

Erythroid precursors develop in bone marrow at rates usually determined by the requirement for sufficient circulating Hb to oxygenate tissues adequately. Erythroid precursors differentiate sequentially from stem cells to progenitor cells to erythroblasts to normoblasts in a process requiring growth factors and cytokines. This process of differentiation requires several days. Normally, erythroid precursors are released into circulation as reticulocytes.

Reticulocytes remain in the circulation for approximately 1 day before reticulin is excised by reticuloendothelial cells with the delivery of the mature erythrocyte into circulation. The mature erythrocyte remains in circulation for about 120 days before being engulfed and destroyed by phagocytic cells of the reticuloendothelial system.

Erythrocytes are highly deformable and increase their diameter from 7 µm to 13 µm when they traverse capillaries with a 3-µm diameter. They possess a negative charge on their surface, which may serve to discourage phagocytosis. Because erythrocytes have no nucleus, they lack a Krebs cycle and rely on glycolysis via the Embden-Meyerhof and pentose pathways for energy. Many enzymes required by the aerobic and anaerobic glycolytic pathways decrease within the cell as it ages. In addition, the aging cell has a decrease in potassium concentration and an increase in sodium concentration. These factors contribute to the demise of the erythrocyte at the end of its 120-day lifespan.

RBCs contain fluid Hb encased in a lipid membrane supported by a cytoskeleton. Abnormalities of the membrane, the chemical composition of the Hb, or certain glycolytic enzymes can reduce the lifespan of RBCs to cause anemia. Basically, only 3 causes of anemia exist: blood loss, increased RBC destruction (hemolysis), and decreased production of RBCs. Each of these 3 causes includes a number of etiologies that require specific and appropriate therapy. Often, the etiology can be determined if the RBCs are altered in either size or shape or if they contain certain inclusion bodies. For example, Plasmodium falciparum malaria is suggested by the presence of more than one ring form in an RBC and produces pan-hemolysis of RBCs of all ages.

Frequency

United States

The prevalence of anemia in population studies of healthy nonpregnant people depends on the Hb concentration chosen for the lower limit of normal values. The World Health Organization chose 12.5 g/dL for both adult males and females. In the United States, limits of 13.5 g/dL for men and 12.5 g/dL for women are probably more realistic. Using these values, approximately 4% of men and 8% of women have values lower than those cited. A significantly greater prevalence is observed in patient populations. Less information is available regarding studies using RBC or Hct.

International

The prevalence of anemia in Canada and northern Europe is believed to be similar to that in the United States. In underprivileged countries, limited studies of purportedly healthy subjects show the prevalence of anemia to be 2-5 times greater than that in the United States. Although geographic diseases, such as sickle cell anemia, thalassemia, malaria, hookworm, and chronic infections, are responsible for a portion of the increase, nutritional factors with iron deficiency and, to a lesser extent, folic acid deficiency play major roles in the increased prevalence of anemia. Populations with little meat in the diet have a high incidence of iron deficiency anemia because heme iron is better absorbed from food than inorganic iron.

A recent study in Iran, however, demonstrated that once-weekly low-dose iron supplementation can be effective in improving iron status and in treating iron deficiency anemia.[1 ]Mozaffari-Khosravi et al randomly selected and assigned 193 adolescent girls aged 14-16 years to receive either 150 mg ferrous sulfate once weekly for 16 weeks or no iron supplementation. Both before and after intervention, the percentage of anemia, iron deficiency anemia, and iron deficiency were measured in both groups of girls.

Although the parameters measured before the intervention were not significantly different, at the end of 16 weeks, the group that received the ferrous sulfate had significant improvement in the same parameters.[1 ]In addition, all cases of iron deficiency anemia were resolved in the gropu receiving the low-dose iron supplementation.

Mortality/Morbidity

The morbidity and mortality of anemias vary greatly depending on the etiology.

o Acute hemorrhage has variable mortality depending on the site of bleeding (80% with aortic rupture, 30-50% with bleeding esophageal varices, approximately 1% with benign peptic ulcers).

o Anemia from gastrointestinal bleeding may be the first evidence of an intestinal malignancy.

o Sickle cell disease may be associated with frequent painful crises and a shortened lifespan, or patients with sickle cell disease may remain relatively asymptomatic with a nearly normal lifespan.

o Most patients with beta-0 homozygous thalassemia die during the second or third decade of life unless they undergo bone marrow transplantation.

o Hereditary spherocytosis either may present with a severe hemolytic anemia or may be asymptomatic with compensated hemolysis.

o Similarly, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may manifest as chronic hemolytic anemia or exist without anemia until the patient receives an oxidant medication.

o The 2-year fatality rate for severe aplastic anemia is 70% without bone marrow transplantation or a response to immunosuppressive therapy.

Many symptoms associated with anemia are not caused by diminished RBC mass. Patients with pernicious anemia are often asymptomatic when they are detected incidentally with an Hb of 6 g/dL. In contrast, ice chewing, calf cramps, and diminished capability to perform muscular work occur in iron-deficiency anemia with an Hb of 10-11 g/dL because of depletion of iron-containing proteins other than Hb.

In addition, tolerance of anemia is proportional to the anemia's rate of development. Symptoms and mortality associated with rapidly developing anemia are more profound than in slowly developing anemia.

Race

Certain races and ethnic groups have an increased prevalence of genetic factors associated with certain anemias. Examples are hemoglobinopathies, thalassemia, and G-6-PD deficiency. Each of these disorders has different morbidity and mortality in different populations due to differences in the genetic abnormality producing the disorder. For example, G-6-PD deficiency and thalassemia have less morbidity in African Americans than in Sicilians because of differences in the genetic fault. Conversely, sickle cell anemia has

a greater morbidity and mortality in African Americans than among Saudi Arabians.

Race is a factor in nutritional anemias and anemia associated with chronic untreated illnesses to the extent that socioeconomic advantages are distributed along racial lines in a given area.[2 ]Socioeconomic advantages affect diet and the availability of health care and lead to a decreased prevalence of these types of anemia.[3,4,5 ]For instance, iron deficiency anemia is much more prevalent in third world populations who have little meat in their diets than it is in populations of the United States and northern Europe. Similarly, anemia of chronic disorders is commonplace in populations with a high incidence of chronic infectious disease (eg, malaria, tuberculosis, AIDS), and this is at least in part worsened by the socioeconomic status of these populations and their access to adequate health care.

Sex

Overall, anemia is twice as prevalent in females as in males. This difference is significantly greater during the childbearing years due to pregnancies and menses.

Approximately 65% of body iron is incorporated into circulating Hb. Each gram of Hb contains 3.46 mg of iron (1 mL of blood with Hb of 15 g/dL = 0.5 mg of iron). Each healthy pregnancy depletes the mother of approximately 500 mg of iron. While a man must absorb about 1 mg of iron to maintain equilibrium, a premenopausal woman must absorb an average of 2 mg daily. Further, because women eat less food than men, they must be more than twice as efficient as men in the absorption of sufficient iron to avoid iron deficiency.

Women have a markedly lower incidence of anemia from X-linked anemias, such as G-6-PD deficiency and sex-linked sideroblastic anemias.

Age

Severe genetically acquired anemias (eg, sickle cell disease, thalassemia, Fanconi syndrome) are more commonly found in children because they do not survive to adulthood.

During the childbearing years, women are more likely to become iron deficient.

Neoplasia increases in prevalence with each decade of life and can produce anemia from bleeding, from the replacement of bone marrow with tumor, or from the development of anemia associated with chronic disorders. Use of

aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and Coumadin increases with age and can produce gastrointestinal bleeding.

ClinicalHistory

Carefully obtain a history and perform a physical examination in every patient with anemia because the findings usually provide important clues to the etiology of the underlying disorder. From the standpoint of the investigation of the anemia, asking questions in addition to those conventionally explored during a routine examination is important. Areas of inquiry found valuable are briefly described below.

Often, the duration of anemia can be established by obtaining a history of previous blood examination and, if necessary, by acquiring those records. Similarly, a history of rejection as a blood donor or prior prescription of hematinics provides clues that anemia was detected previously.

Obtain a careful family history not only for anemia but also for jaundice, cholelithiasis, splenectomy, bleeding disorders, and abnormal Hbs. Carefully document the patient's occupation, hobbies, prior medical treatment, drugs (including over-the-counter medications and vitamins), and household exposures to potentially noxious agents. Patients are unlikely to volunteer exposures to tranquilizers, insecticides, paints, solvents, and hair dyes unless specifically queried.

In searching for blood loss, carefully document pregnancies, abortions, and menstrual loss. Estimates of menstrual losses are notoriously inaccurate if only routine inquiry is made.

Often, patients do not appreciate the significance of tarry stools. Changes in bowel habits can be useful in uncovering neoplasms of the colon.

Hemorrhoidal blood loss is difficult to quantify, and it may be overlooked or overestimated from one patient to another. Obviously, seek a careful history of gastrointestinal complaints that may suggest gastritis, peptic ulcers, hiatal hernias, or diverticula.

Abnormal urine color can occur in renal and hepatic disease and in hemolytic anemia.

A thorough dietary history is important in a patient who is anemic. This history must include foods that the patient both eats and avoids as well as an estimate of their quantity.

o A meal-by-meal description is necessary to obtain appropriate estimates.

o Even then, patients frequently attempt to deceive the physician because of embarrassment regarding dietary idiosyncrasies or financial restrictions. In these circumstances, a close and concerned family member participating in the dietary history can often be helpful because this person is usually more objective than the patient.

o Specifically question patients regarding consumption of either clay or laundry starch. This history will not be provided spontaneously. These substances render iron less absorbable.

o Changes in body weight are important with regard to dietary intake and can suggest the presence of malabsorption or an underlying wasting disease of infectious, metabolic, or neoplastic origin.

Nutritional deficiencies may be associated with unusual symptoms that can be elicited by a history.

o Patients with iron deficiencies frequently chew or suck ice (pagophagia). Occasionally, they complain of dysphasia, brittle fingernails, relative impotence, fatigue, and cramps in the calves on climbing stairs that are out of proportion to their anemia.

o In vitamin B-12 deficiency, early graying of the hair, a burning sensation of the tongue, and a loss of proprioception are common.

o Suspect a loss of proprioception if the patient stumbles in the dark or must look in order to put on pants in the morning.

o Paresthesia or unusual sensations frequently described as pain also occur in pernicious anemia.

o Patients with folate deficiencies may have a sore tongue, cheilosis, and symptoms associated with steatorrhea.

o Color, bulk, frequency, and odor of stools and whether the feces float or sink can be helpful in detecting malabsorption. More sensitive questions to detect steatorrhea include whether the toilet needs to be flushed more than once to rid it of stool and whether an oily substance is floating on the water surface after the first flush.

Obtain a history of fever or identify the presence of fever because infections, neoplasms, and collagen vascular disease can cause anemia. Similarly, the occurrence of purpura, ecchymoses, and petechiae suggest the occurrence of either thrombocytopenia or other bleeding disorders; this may be an indication either that more than one bone marrow lineage is involved or that coagulopathy is a cause of the anemia because of bleeding.

Cold intolerance can be an important symptom of hypothyroidism or lupus erythematosus, paroxysmal cold hemoglobinuria, and certain macroglobulinemias.

The relation of dark urine to either physical activity or time of day can be important in march hemoglobinuria and paroxysmal nocturnal hemoglobinuria.

Explore the presence or the absence of symptoms suggesting an underlying disease, such as cardiac, hepatic, and renal disease; chronic infection; endocrinopathy; or malignancy.

Physical

Too often, the physician rushes into the physical examination without looking at the patient for an unusual habitus or appearance of underdevelopment, malnutrition, or chronic illness. These findings can be important clues to the underlying etiology of disease and provide information related to the duration of illness. The skin and mucous membranes are often bypassed so that pallor, abnormal pigmentation, icterus, spider nevi, petechiae, purpura, angiomas, ulcerations, palmar erythema, coarseness of hair, puffiness of the face, thinning of the lateral aspects of the eyebrows, nail defects, and a usually prominent venous pattern on the abdominal wall are missed in the rush to examine the heart and the lungs.

Examine optic fundi carefully but not at the expense of the conjunctivae and the sclerae, which can show pallor, icterus, splinter hemorrhages, petechiae, comma signs in the conjunctival vessels, or telangiectasia that can be helpful in planning additional studies.

Perform systematic examination for palpable enlargement of lymph nodes for evidence of infection or neoplasia. Bilateral edema is useful in disclosing underlying cardiac, renal, or hepatic disease, whereas unilateral edema may portend lymphatic obstruction due to a malignancy that cannot be observed or palpated.

Carefully search for both hepatomegaly and splenomegaly. Their presence or absence is important, as are the size, the tenderness, the firmness, and the presence or the absence of nodules. In patients with chronic disorders, these organs are firm, nontender, and nonnodular. In patients with carcinoma, they may be hard and nodular. The patient with an acute infection usually has a palpably softer and more tender organ.

A rectal and pelvic examination cannot be neglected because tumor or infection of these organs can be the cause of anemia.

The neurologic examination should include tests of position sense and vibratory sense, examination of the cranial nerves, and testing for tendon reflexes. The heart should not be ignored because enlargement may provide

evidence of the duration and the severity of the anemia, and murmurs may be the first evidence of a bacterial endocarditis that could explain the etiology of the anemia.

Causes

Causes of anemia are numerous and multifaceted. A family history may be useful in detecting hereditary etiology. Diet and exposure to drugs and chemicals can be useful. A geographic history and a thorough knowledge of the patient's health can be important in establishing an etiology.

Genetico Hemoglobinopathieso Thalassemiaso Enzyme abnormalities of the glycolytic pathwayso Defects of the RBC cytoskeletono Congenital dyserythropoietic anemiao Rh null diseaseo Hereditary xerocytosiso Abetalipoproteinemiao Fanconi anemia

Nutritionalo Iron deficiencyo Vitamin B-12 deficiencyo Folate deficiencyo Starvation and generalized malnutrition

Hemorrhage Immunologic - Antibody-mediated abnormalities Physical effects

o Traumao Burnso Frostbiteo Prosthetic valves and surfaces

Drugs and chemicalso Aplastic anemiao Megaloblastic anemia

Chronic diseases and malignancieso Renal diseaseo Hepatic disease

o Chronic infectionso Neoplasiao Collagen vascular diseases

Infectionso Viral - Hepatitis, infectious mononucleosis, cytomegaloviruso Bacterial - Clostridia, gram-negative sepsiso Protozoal - Malaria, leishmaniasis, toxoplasmosis

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

Differential DiagnosesAplastic Anemia Myelophthisic AnemiaCooley Anemia Pernicious AnemiaHemolytic Anemia Sickle Cell AnemiaIron Deficiency Anemia Spur Cell AnemiaLow LDL Cholesterol (Hypobetalipoproteinemia) Thalassemia, AlphaMegaloblastic Anemia Thalassemia, Beta

WorkupLaboratory Studies

The first step in the diagnosis of anemia is detection with reliable accurate tests so that important clues to underlying disease are not overlooked and patients are not subjected to unnecessary tests for and treatment of nonexistent anemia. Detection of anemia involves the adoption of arbitrary criteria.

The World Health Organization's criterion for anemia in adults is Hb values less than 12.5 g/dL. Children aged 6 months to 6 years are considered anemic at Hb levels less than 11 g/dL, and children aged 6-14 years are considered anemic when Hb levels are less than 12 g/dL. The disadvantage of such arbitrary criteria is that a few healthy individuals fall below the reference range, and some people with an underlying disorder fall within the reference range for Hb concentration.

Usually, US values are slightly higher. Anemia is suggested in males with Hb levels less than 13.5 g/dL and in females with Hb levels less than 12.5 g/dL. Higher values are anticipated in individuals living in altitudes significantly above sea level. Conditions with an increase in plasma volume, such as during

the last trimester of pregnancy, are associated with lower values without an existent anemia because the red cell mass is normal.

Once the existence of anemia is established, investigate the pathogenesis. If an adequate history has been taken and a physical examination has been performed, the etiology may be obvious, and confirmatory studies and appropriate therapy can be undertaken with a minimum of investigation. If this is not the case, initiate a definite plan of investigation considering the cost to the patient along with a determination of the etiology of the abnormality.

A rational approach is to begin by examining the peripheral smear and laboratory values obtained on the blood count. If the anemia is either microcytic (mean corpuscular volume [MCV], <84) or macrocytic (MCV, >96) or if certain abnormal RBCs or WBCs are observed in the blood smear, the investigative approach can be limited (see Table 1, Table 2, and Table 3).

Presently, RBC cellular indices are computer calculated and automatically placed on laboratory reports. The formulae for calculating these values follow (reference ranges are in parentheses). RBC is per million cells.

MCV = Hct X 10/RBC (84-96 fL) Mean corpuscular Hb (MCH) = Hb X 10/RBC (26-36 pg) Mean corpuscular Hb concentration (MCHC) = Hb X 10/Hct (32-36%)

A rapid method of determining whether cellular indices are normocytic and normochromic is to multiply the RBC and Hb by 3. The RBC multiplied by 3 should equal the Hb, and the Hb multiplied by 3 should equal the Hct. Deviation from the calculated values suggests microcytosis, macrocytosis, or hypochromia versus the presence of spherocytes (MCHC, >36).

Table 1. Microcytic Hypochromic Anemia (MCV, <83; MCHC, <31)

Condition Serum Iron

Total Iron-Binding Capacity (TIBC)

Bone Marrow

IronComment

Iron deficiency ↓ ↑ 0 Responsive to iron therapyChronic inflammation

↓ ↓ ++ Unresponsive to iron therapy

Thalassemia major

↑ N ++++ Reticulocytosis and indirect bilirubinemia

Thalassemia minor

N N ++ Elevation of A of fetal hemoglobin, target cells, and poikilocytosis

Lead poisoning N N ++ Basophilic stippling of RBCs

Sideroblastic ↑ N ++++ Ring sideroblasts in marrowHemoglobin N N ++ Hemoglobin electrophoresis↓ = decreased; ↑ = increased; 0 = absent; +'s indicate the amount of stainable iron in bone marrow specimens, on a scale of 0-4; N = normal.

  Table 2. Macrocytic Anemia (MCV, >95)Megaloblastic bone marrow Deficiency of vitamin B-12

Deficiency of folic acidDrugs affecting DNA synthesisInherited disorders of DNA synthesis

Nonmegaloblastic bone marrow Liver diseaseHypothyroidism and hypopituitarismAccelerated erythropoiesis (reticulocytes)Hypoplastic and aplastic anemiaInfiltrated bone marrow

Table 3. Various Forms of RBCsMacrocyte Larger than normal (>8.5 µm diameter). See Table 2.Microcyte Smaller than normal (<7 µm diameter). See Table 1.Hypochromic Less hemoglobin in cell. Enlarged area of central pallor. See Table

1.Spherocyte Loss of central pallor, stains more densely, often microcytic.

Hereditary spherocytosis and certain acquired hemolytic anemias.Target cell Hypochromic with central "target" of hemoglobin. Liver disease,

thalassemia, hemoglobin D, postsplenectomy.Leptocyte Hypochromic cell with a normal diameter and decreased MCV.

Thalassemia.Elliptocyte Oval to cigar shaped. Hereditary elliptocytosis, certain anemias

(particularly vitamin B-12 and folate deficiency).Schistocyte Fragmented helmet- or triangular-shaped RBCs. Microangiopathic

anemia, artificial heart valves, uremia, malignant hypertension.

Stomatocyte Slitlike area of central pallor in erythrocyte. Liver disease, acute alcoholism, malignancies, hereditary stomatocytosis, and artifact.

Tear-shaped RBCs

Drop-shaped erythrocyte, often microcytic. Myelofibrosis and infiltration of marrow with tumor. Thalassemia.

Acanthocyte Five to 10 spicules of various lengths and at irregular interval on surface of RBCs.

Echinocyte Evenly distributed spicules on surface of RBCs, usually 10-30. Uremia, peptic ulcer, gastric carcinoma, pyruvic kinase deficiency, preparative artifact.

Sickle cell Elongated cell with pointed ends. Hemoglobin S and certain types of hemoglobin C and l.

In microcytic hypochromic anemia, seek a source of bleeding. The appropriate laboratory tests are serum iron level and TIBC and either serum ferritin level or stain of bone marrow specimen for iron. If the serum iron level is decreased and TIBC is increased, a diagnosis of iron deficiency can be made, therapy can be initiated, and a search for the cause of the iron deficiency can be started. If this cannot be demonstrated, suspect each of the other causes of a microcytic anemia listed in Table 1, and the order of investigation can be influenced by findings in the history, physical examination, or peripheral smear.

Similarly, a reasonable approach with macrocytic anemia is to determine if the bone marrow aspirate is megaloblastic. If so, attempt to incriminate either vitamin B-12 or folic acid deficiency with appropriate laboratory studies. Similar to the establishment of a diagnosis of iron deficiency anemia, a diagnosis of vitamin B-12 or folic acid deficiency does not stop with an abnormal laboratory value for one of these vitamins. Prompt treatment can be instituted, but a continued search for an underlying cause of the vitamin deficiency is indicated (see Pernicious Anemia).

When a normocytic normochromic anemia is encountered, classify the anemia into 3 possible etiologies (ie, blood loss, hemolysis, decreased production). In most anemias, one of these causes is the dominant factor. However, in certain anemias, more than a single cause may play an important role. For example, pernicious anemia is predominantly due to decreased production of erythrocytes, but hemolysis adds significantly to the severity of anemia.

Blood loss

Obviously, significant hemorrhage produces anemia. Immediately after blood loss, the Hct cannot be used as a reliable method to determine the quantity of lost blood because the patient loses plasma as well as RBCs. After acute hemorrhage, the Hct falls for 24-48 hours until the plasma volume is replaced. At that time, anemia is normochromic and normocytic with normal cellular indices because the cells in the peripheral blood have been produced prior to bleeding (see Iron Deficiency Anemia).

If the patient had adequate iron stores, accelerated production of RBCs occurs, so that 1 week after bleeding, a larger than normal number of young RBCs and reticulocytes are circulating in the peripheral blood. Because reticulocytes and young RBCs have a larger volume (MCV of approximately 120), macrocytes may be observed in the peripheral smear, and a slight increase in the MCV occurs.

If hemorrhage was sufficient to deplete iron stores (1-2 L of blood, 500-1000 mg of iron), newly formed erythrocytes are microcytic and hypochromic and gradually replace normal erythrocytes in the circulation that were produced prior to the induction of iron deficiency. Because RBCs normally survive for 120 days in circulation, maximal changes in the MCV and MCHC are not observed until that time. Iron deficiency and the depletion of iron stores can be detected several weeks after bleeding by measurements of the serum iron level and TIBC and/or special stains of bone marrow specimens showing an absence of storage iron.

Diagnosis of iron deficiency anemia in an adult in the United States should be attributed to bleeding unless other causes can be proven. Aside from recent multiparity, other causes are relatively uncommon and include prolonged dietary idiosyncrasies (eg, clay eating, laundry starch consumption, protein deprivation for several years), urinary loss of iron due to intravascular hemolysis (eg, artificial aortic valves, paroxysmal nocturnal hemoglobinuria), gastrectomy, and other upper gastrointestinal surgery or disease.

Diagnosis of iron deficiency anemia is made by demonstrating that the patient has low serum iron levels and elevated TIBC, absence of stainable iron in a bone marrow specimen, or both. A low serum ferritin level provides confirmation of the diagnosis. The presence of microcytosis and hypochromia is helpful but not diagnostic.

Microcytic hypochromic anemia is observed with conditions other than iron deficiency anemia. Certain types of these disorders are iron-overloading states in which the administration of iron can be deleterious to the patient (see Table 1). Similarly, low serum iron levels can be observed in chronic inflammatory states with normal body stores of iron. However, in the latter, the TIBC is

usually decreased rather than increased, and stainable iron can be demonstrated in bone marrow aspirates. Whenever the diagnosis of iron deficiency anemia is in doubt, follow-up blood work after administration of iron to show correction of the anemia can be helpful in confirming the diagnosis.

The patient notices hemorrhage from most body organs. Epistaxis, hemoptysis, or hematuria of sufficient degree to cause anemia is usually reported to the physician long before iron deficiency ensues. However, bleeding from either the uterus or the gastrointestinal tract may be disregarded by the patient or be totally undetected until anemia becomes profound and symptomatic.

Menstrual bleeding among healthy females varies monthly from 10-250 mL. Unless the patient observes a change in menses, she relates that menses are normal unless specific questions are asked. The presence of clots, abdominal cramps, excessive gushing of blood upon removal of tampons, the need for both tampons and pads, and the use of an unusual number of pads or tampons can be used to determine if menstrual bleeding may be sufficient to induce iron deficiency anemia.

Gastrointestinal bleeding is the other occult cause of anemia due to blood loss. If hemorrhage is profuse, it is usually detected before evidence of iron deficiency anemia occurs because hematochezia or melena causes the patient to seek medical attention. However, if the bleeding occurs slowly, it is usually undetected until anemia ensues because stools appear normal.

Every patient with iron deficiency anemia should have a stool examination for occult blood. A positive result necessitates a careful search of the gastrointestinal tract to identify the site of bleeding. Unfortunately, a negative result does not exclude gastrointestinal blood loss because bleeding can be intermittent and require several examinations for detection. Also, less than 20-30 mL of blood in the stool per day may go undetected due to the insensitivity of the test. The 2 methods used to detect small daily losses of blood from the gut are as follows: (1) placing the patient on a meat-free diet for several days and using more sensitive methods, such as a benzidine test, and (2) labeling the patient's RBCs with chromium 51 and collecting stool specimens for the detection of the radioisotope.

Investigate gastrointestinal bleeding by endoscopy and radiographic studies (see Procedures).

Hemolysis (increased RBC destruction)

A normal RBC survives in the circulation for 120 days. If the erythrocytic lifespan is shortened significantly (<40 d), the patient has a hemolytic disorder that may be demonstrated by showing increased production of erythrocytes, increased destruction, or both. The former is revealed most readily by the presence of sustained reticulocytosis and the latter by the occurrence of indirect bilirubinemia (see Table 4, below).

Other laboratory tests are available to detect hemolysis, but they are either more expensive or less reliable.

Table 4. Classification of the Hemolytic Disorders

Hereditary AcquiredIntracorpuscular defect

Hereditary spherocytosisHereditary elliptocytosisHemoglobinopathiesThalassemiasCongenital dyserythropoietic anemiasHereditary RBC enzymatic deficienciesRarer hereditary abnormalities

Vitamin B-12 and folic acid deficiencyParoxysmal nocturnalHemoglobinuriaSevere iron deficiency

Extracorpuscular defect

Physical agents: Burns, cold exposureTraumatic: Prosthetic heart valves, march hemoglobinemia, DIC, graft rejectionChemicals: Drugs and venomsInfectious agents: Malaria, toxoplasmosis, mononucleosis, hepatitis, primary atypical pneumonia, clostridial infections, bartonellosis, leishmaniasisHepatic and renal diseaseCollagen vascular diseaseMalignancies: Particularly hematologic neoplasiaTransfusion of incompatible bloodHemolytic disease of the newborn

Cold hemagglutinindiseaseAutoimmune hemolytic anemia Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)

Anemia solely due to hemolysis does not occur until RBCs are being destroyed at 6-8 times the normal rate, reducing the mean RBC lifespan to less than 20 days because of the bone marrow's capacity to undergo 6-fold hypertrophy and hyperplasia. Thus, if the clinician relies on the presence of anemia to detect hemolytic states, the clinician misses most of them and, perhaps, an important clue to an underlying disorder. On the contrary, if reticulocytosis and indirect bilirubinemia are used to detect hemolytic states, they are usually found when the mean lifespan is less than 40-50 days. More sophisticated methods, such as measurements of RBC lifespan, are required to detect less severe shortening of erythrocyte lifespan (50-100 d) and are only occasionally needed in clinical practice.

All patients with both reticulocytosis and indirect bilirubinemia have a hemolytic disorder. All patients with sustained reticulocytosis have a hemolytic disorder. Unfortunately, the contrary is not the case, and significant hemolysis can occur without reticulocytosis if the bone marrow is unable to produce cells at an accelerated rate (eg, pernicious anemia, leukemia, aplasia). A single demonstration of an elevated reticulocyte count is insufficient to establish a diagnosis of hemolysis because transient reticulocytosis may occur without hemolysis (eg, in the treatment of iron deficiency anemia).

Almost all patients with indirect bilirubinemia have a hemolytic disorder. In adults, the exception is patients with Gilbert disease. These patients can be distinguished from those with hemolytic disorders and those who have no other obvious stigmata of hemolysis (eg, anemia, reticulocytosis, Coombs test) by having the patient fast for 3 days. In Gilbert disease, indirect bilirubin doubles with starvation, whereas in hemolytic disorders, it does not. Once the presence of hemolysis has been established, the etiology of the increased rate of RBC destruction can be sought.

All causes of hemolytic disorders are either hereditary or acquired. Similarly, they are due to either an intrinsic abnormality of the RBC (intracorpuscular defect) or external factors that shorten the erythrocyte lifespan (extracorpuscular). Using this

nomenclature, only 4 groups of hemolytic disorders are possible—hereditary intracorpuscular, hereditary extracorpuscular, acquired intracorpuscular, and acquired extracorpuscular.

All hereditary hemolytic disorders are due to intracorpuscular defects, and most acquired disorders are due to extracorpuscular abnormalities (see Table 4). Hereditary etiologies of hemolytic disease are suggested strongly in any patient with a family history of anemia, jaundice, cholelithiasis, or splenectomy. Whenever possible, family members, particularly parents, siblings, and children, should undergo a hematologic examination, including hemogram with reticulocyte count, indirect bilirubin determination, and careful examination of the peripheral smear.

If a specific hereditary hemolytic disorder (eg, hereditary spherocytosis, hemoglobinopathy) is suggested in a patient, examine blood from family members for that entity by appropriate laboratory methods. Establishment of a hemolytic defect in other closely related family members permits a presumptive diagnosis of hereditary intracorpuscular hemolytic disorder in the patient. Showing a similar RBC abnormality (eg, spherocytes, abnormal Hb, G-6-PD deficiency) among family members establishes the basic etiology. Once the probability of a hereditary hemolytic disorder is established, a planned approach to determine the definitive abnormality is usually simple.

A careful examination of the peripheral smear may reveal spherocytes in hereditary spherocytosis; ovalocytes in hereditary elliptocytosis; sickle cells in patients with major hemoglobinopathies associated with sickle Hb; target cells in patients with Hb C or E disease; and marked poikilocytosis with target cells, microcytes, and hypochromic RBCs in thalassemia.

Even in certain rare disorders, abnormal erythrocyte morphology may provide an important clue. Examples are acanthocytosis in abetalipoproteinemia, stomatocytosis in the hereditary disorder of this name, and numerous target cells in lecithin cholesterol acyltransferase deficiency. Other laboratory studies of value in the hereditary hemolytic disorders include the following:[6 ]

Hereditary spherocytosis - MCHC greater than 36%, incubated osmotic fragility studies autohemolysis in oxalate, and detection of the underlying molecular defect

Hemoglobinopathies - Sickle cell preparation, Hb electrophoresis at one or more pH, heat denaturation test for unstable Hbs, oxygen disassociation for Hbs with abnormal oxygen affinity

Thalassemia - A2 and fetal Hb, Hb electrophoresis, characterization of the molecular defect, quantification of alpha and beta chains

Congenital dyserythropoietic anemias - Demonstration of abnormalities of erythroid precursors in bone marrow aspirates, positive acid hemolysis (Ham) test with normal result of sucrose hemolysis test in one form of this disease (hereditary erythroblastic multinuclearity with a positive acidified serum test [HEMPAS])

Hereditary RBC enzymatic deficiencies - Specific RBC enzyme assay

In clinical practice, approximately 90% of hereditary RBC enzymatic deficiencies with significant clinical manifestations are either G-6-PD deficiencies or abnormalities of pyruvic kinase. The age at which a hemolytic disorder is detected is not always helpful in determining whether the disorder is hereditary. Although the abnormality is inherited, congenital manifestations may be unusual. An infant with sickle cell anemia or beta thalassemia appears healthy at birth. Clinical manifestations usually do not occur in infants younger than 6 months because fetal Hb has not been replaced by adult Hb until that age. Most patients with G-6-PD deficiency have no manifestations of the erythrocyte enzymatic abnormality until they receive an oxidant drug.

Usually, thalassemia minor is not detected until a routine hemogram is performed, and, then, it is often mistaken for iron deficiency anemia because of the microcytosis and hypochromia. Thus, the physician dealing with adult patients must be as aware of these disorders as the pediatrician.

The most commonplace of the hereditary disorders is G-6-PD deficiency because it occurs in 10% of the African American population living in the United States. In this population, G-6-PD deficiency usually remains undetected until oxidant drugs are administered. Then, it produces a mild-to-moderate hemolytic anemia that is transient in nature. In white populations of Mediterranean derivation, G-6-PD deficiency can produce a chronic hemolytic anemia without exposure to drugs. Exposure to oxidant drugs can produce lethal hemolysis.

Acquired hemolytic disorders occur in a large number of disease states and can vary considerably in severity. In addition, hemolysis may be observed as a result of physical injury to the RBC or following exposure to drugs, chemicals, or venoms. In many patients, the etiology of the hemolytic disorder is apparent because of other manifestations of the disease (eg, infections, collagen vascular disease).

A confirmed positive Coombs test result can be extremely helpful in this group of disorders. It provides assurance that the hemolytic disorder is an acquired extracorpuscular defect and limits it to the group of disorders associated with autoimmune hemolytic anemia. They include the following:

Drug-dependent antibodies (eg, to penicillin, quinidine, alpha methyldopa) Coexistence of an underlying disease (eg, hematologic malignancies, lupus

erythematosus, certain viral infections) Idiopathic groups in which an underlying disease cannot be demonstrated

Usually, the acquired hemolytic disorders with intracorpuscular defects are not difficult to diagnose. Vitamin B-12 and folic acid deficiencies are associated with macrocytic anemia, the presence of hypersegmented polymorphonuclear leukocytes in the peripheral smear, megaloblastic bone marrow, physical findings of the underlying cause of the deficiency state, and abnormal serum levels for the deficient vitamin.

Iron deficiency in the United States is rarely of sufficient severity to cause significant hemolysis and is merely mentioned herein for the sake of completeness.

Paroxysmal nocturnal hemoglobinuria is diagnosed only if the physician considers it in the differential diagnosis, and it may manifest by either a pancytopenia or a hemoglobinuria. However, a sugar-water test can help exclude this cause of hemolysis.

The major diagnostic problem encountered with hemolytic disorders is when the known causes for hemolysis have been excluded by history, physical examination, and laboratory studies; the Coombs test result is negative; and not enough family members can be tested to differentiate between hereditary intracorpuscular hemolytic disorders and acquired extracorpuscular defects.

A donor cell chromium survival study can be helpful in differentiating between a hereditary hemolytic disorder and an acquired hemolytic disorder. Labeled RBCs from a healthy blood donor of a compatible blood group allow for a normal survival rate in patients with hereditary hemolytic disease and a shortened lifespan in those with an acquired extracorpuscular defect.

Decreased RBC production

Diminished production of RBCs is suggested in all patients without evidence of either blood loss or hemolysis. Thus, a patient with anemia without evidence of

bleeding or iron deficiency with normal indirect bilirubin and normal or decreased reticulocyte count probably has a defect in the production of erythrocytes. Many of these patients have pancytopenia or other abnormalities of the leukocytes or the platelets that can be detected with an examination of a peripheral smear. When this group of disorders is suspected, the most important laboratory test is a bone marrow biopsy and aspiration (see Procedures). The bone marrow biopsy permits categorization of these disorders into 3 separate groups, as shown in the image below: (1) aplastic or hypoplastic, (2) hyperplastic, and (3) bone marrow replaced with nonhematopoietic elements (infiltration of bone marrow).

Anemia. Decreased production of red blood cells is suggested in certain patients with anemia. Bone marrow biopsy specimen allows categorization of patients with anemia without evidence of blood loss or hemolysis into 3 groups: aplastic or hypoplastic disorder, hyperplastic disorder, or infiltration disorder. Each category and its associated causes are listed in this image.

Drugs or chemicals commonly cause the aplastic and hypoplastic group of disorders. Certain types of these causative agents are dose related and others are idiosyncratic. Any human exposed to a sufficient dose of inorganic arsenic, benzene, radiation, or the usual chemotherapeutic agents used for treatment of neoplastic diseases develops bone marrow depression with pancytopenia. Conversely, among the idiosyncratic agents, only an occasional human exposed to these drugs has an untoward reaction resulting in suppression of 1 or more of the formed elements of bone marrow (1:100 to 1:millions). With certain types of these drugs, pancytopenia is more common, whereas with others, suppression of one cell line is usually observed. Thus, chloramphenicol may produce pancytopenia, whereas a granulocytopenia is more frequently observed with toxicity to sulfonamides or antithyroid drugs.

The idiosyncratic causes of bone marrow suppression include multiple drugs in each of the categories that can be prefixed with anti- (eg, antibiotics, antimicrobials, anticonvulsants, antihistamines). The other idiosyncratic causes of known etiology are viral hepatitis and paroxysmal nocturnal hemoglobinuria. In approximately one

half of patients presenting with aplastic anemia, a definite etiology cannot be established, and the anemia must be regarded as idiopathic.

Whenever possible, a cause for the aplastic anemia should be uncovered because cessation of exposure may lead to recovery. Identification of the offending agent is likewise important in determining the prognosis.

Chances of survival are poorer for patients with idiosyncratic aplasia caused by chloramphenicol and viral hepatitis and better when paroxysmal nocturnal hemoglobinuria or anti-insecticides are the probable etiology. The prognosis for idiopathic aplasia lies between these 2 extremes, with an untreated mortality rate of approximately 60-70% within 2 years after diagnosis.

Rare causes of anemia due to a hypoplastic bone marrow include familial disorders and the acquired pure red cell aplasias. The latter are characterized by a virtual absence of erythroid precursors in the bone marrow with normal numbers of granulocytic precursors and megakaryocytes.

Among patients with a hyperplastic bone marrow and decreased production of RBCs, one group has an excellent prognosis, and the other is unresponsive, refractory to therapy, and has a relatively poor prognosis. The former includes patients with disorders of relative bone marrow failure due to nutritional deficiency in whom proper treatment with vitamin B-12, folic acid, or iron leads to a correction of anemia once the appropriate etiology is established. Drugs acting as an antifolic antagonist or inhibitor of DNA synthesis can produce similar effects. The second group includes patients with an idiopathic hyperplasia that may respond partially to pyridoxine therapy in pharmacologic doses but, more frequently, does not. These patients have ringed sideroblasts in the bone marrow indicating an inappropriate use of iron in the mitochondria for heme synthesis.

Certain patients with marrow hyperplasia may have refractory anemia for years, but some of the group eventually develop acute myelogenous leukemia.

Rare causes of diminished erythrocyte production with hyperplastic bone marrow include hereditary orotic aminoaciduria and erythremic myelosis.

Infiltration of the bone marrow with fibrous tissue, neoplastic cells, or other cells that replace normal hematopoietic tissue can diminish the production of RBCs, granulocytes, and platelets.[7 ]The diagnosis of myelofibrosis or neoplastic involvement of bone marrow is often suggested by evidence of myeloid metaplasia

in the peripheral smear (ie, erythroid and granulocyte precursors). Replacement of bone marrow with nonhemopoietic cells leads to activation of fetal sites of blood production in organs, such as the liver and the spleen, with release of abnormally shaped erythrocytes and normoblasts, immature granulocytes and normoblasts, immature granulocytes, and large platelets into the peripheral blood. Myeloid metaplasia does not occur in aplastic disease. Thus, its presence in a patient who is anemic suggests bone marrow infiltration, even before the biopsy specimen is obtained.

Imaging Studies

Imaging studies are useful in the workup for anemia when a neoplastic etiology is suggested. They permit discovery of the neoplasm or centrally located adenopathy. Occasionally, they are useful in detecting or confirming the existence of splenomegaly.

Procedures

Investigate gastrointestinal bleeding by endoscopy and radiographic studies to identify the bleeding site. However, even these methods may leave a source of gastrointestinal bleeding undetected because these procedures do not detect the bleeding site or the lesion if small. Examples of these causes include coagulation abnormalities induced by aspirin or platelet dysfunction, hookworm infestation, hemangiomas of the small bowel, lymphosarcoma and other tumors, adenomas of the gallbladder, and self-administration of anticoagulants.

Bone marrow aspirates and biopsy findings are particularly useful in establishing the etiology of anemia in patients with decreased production of RBCs. They help differentiate aplasia; megaloblastic hyperplasia; and infiltration of marrow with neoplasia, myelodysplasia, and myelofibrosis. In addition, they lead to a definitive histologic diagnosis of leukemias, lymphomas, myelomas, and metastatic carcinomas. These procedures are less useful in detecting hemolytic anemia (except to detect lymphoma or leukemia), and they are less useful in diagnosing congenital dyserythropoietic anemia, in which they reveal the multinuclearity of erythroid precursors. Iron stains of the bone marrow aspirate can be used to document the existence of iron deficiency anemia or the sideroblastic anemias.

Treatment

Medical Care

The purpose of establishing the etiology of an anemia is to permit selection of a specific and effective therapy.

Transfusion of packed RBCs should be reserved for patients who are actively bleeding and for patients with a severe and symptomatic anemia.[8 ]Transfusion is palliative and should not be used as a substitute for specific therapy. In chronic diseases associated with anemia of chronic disorders, erythropoietin may be helpful in averting or reducing transfusions of packed RBCs.

The appropriate treatment of anemia due to blood loss is correction of the underlying condition and oral administration of ferrous sulfate until the anemia is corrected and for several months afterward to ensure that body stores are replete with iron. Relatively few indications exist for the use of parenteral iron therapy, and blood transfusions should be reserved for the treatment of shock or hypoxia.

Nutritional therapy is used to treat deficiency of iron, vitamin B-12, and folic acid. Pyridoxine may be useful in the treatment of certain patients with sideroblastic anemia, even though this is not a deficiency disorder.

Corticosteroids are useful in the treatment of autoimmune hemolytic anemia. Treatment of aplastic disorders includes removal of the offending agent

whenever it can be identified, supportive therapy for the anemia and thrombocytopenia, and prompt treatment of infection. Avoid transfusion in patients with a potential bone marrow donor because transfusion worsens the probability of cure from transplantation. Certain patients seem to develop a salutary response with immunosuppressive therapy (ie, antithymocyte globulin, cyclosporin). Splenectomy may provide sufficient improvement for patients with hypoplastic, but not totally aplastic, marrow so that transfusion is not necessary, and platelet and granulocyte counts increase to less dangerous levels (see Surgical Care).

Therapy and medical care vary considerably in the group of hereditary disorders. Splenectomy has been advantageous in hereditary spherocytosis and hereditary elliptocytosis, in some of the unstable hemoglobinopathies, and in certain patients with pyruvic kinase deficiency. It has little value in most other hereditary hemolytic disorders (see Surgical Care).

Patients with beta-thalassemia major and the major hemoglobinopathies associated with sickle Hb usually require medical attention at frequent intervals for the treatment of anemia, infection, pain, and leg ulcers because of

the serious nature of these illnesses. Conversely, many of the other hereditary abnormalities have minimal or no clinical manifestations; the patient only requires reassurance.

Drugs and chemicals capable of producing aplasia or a maturation arrest of erythroid precursors should be discontinued and avoided. Similarly, diseases known to be associated with anemia should be appropriately treated.

Guidelines related to the treatment of chemotherapy-associated anemia and CME related to these guidelines are available.

Surgical Care

Surgery is useful to control bleeding in patients who are anemic. Most commonly, bleeding is from the gastrointestinal tract, the uterus, or the bladder. Patients should be hemodynamically stable before and during surgery. A blood transfusion may be needed.

Splenectomy is useful in the treatment of autoimmune hemolytic anemias and in certain hereditary hemolytic disorders (ie, hereditary spherocytosis and elliptocytosis, certain unstable Hb disorders, pyruvic kinase deficiency). Improvement in survival rates has been reported in patients with aplastic anemia, but splenectomy is not the preferential therapy. Leg ulcers have shown improvement in some patients with thalassemia. Prior to splenectomy, patients should be immunized with polyvalent pneumococcal vaccine. Preferably, this should be administered more than 1 week prior to surgery.

Bone marrow and stem cell transplantation have been used in patients with leukemia, lymphoma, Hodgkin disease, multiple myeloma, myelofibrosis, and aplastic disease. Survival rates improved, and hematologic abnormalities were corrected. Allogeneic bone marrow transplantation successfully corrected phenotypic expression of sickle cell disease and thalassemia and provided enhanced survival in patients who survive transplantation.

Consultations

Surgical consultation is indicated to control bleeding, for splenectomy when necessary, and for biopsies to establish the presence of neoplasia.

Consultation with gastroenterologists is frequently sought to identify a bleeding site in the gut.

Urologic consultation may be needed to investigate hematuria.

Diet

Iron deficiency anemia is prevalent in geographic locations where little meat is in the diet. Many of these locations have sufficient dietary inorganic iron to equal the iron content in persons residing in countries in which meat is eaten. However, heme iron is more efficiently absorbed than inorganic food iron.

A strict vegetarian diet requires iron and vitamin B-12 supplementation. Folic acid deficiency occurs among people who consume few leafy

vegetables. Coexistence of iron and folic acid deficiency is common among Third World

nations.

Activity

The activity of patients with severe anemia should be curtailed until the anemia is partially corrected. Transfusion can often be avoided by ordering bed rest, while therapy is initiated for a patient with correctable anemia (eg, pernicious anemia).

March hemoglobinuria is a rare hemolytic disorder usually observed in young males. Individuals develop hemoglobinuria after marching or running on hard surfaces. Curtailing the precipitating exercise (ie, running on grass rather than concrete) and using shoes with reinforced soles are helpful in preventing hemoglobinuria.

MedicationDocumentation of the etiology of anemia is essential in the selection of therapy. All microcytic anemias are not caused by iron deficiency; some are iron-overloading disorders. Similarly, all megaloblastic anemias are not associated with either vitamin B-12 deficiency or folic acid deficiency. Hereditary hemolytic disorders do not improve with corticosteroid therapy. Specific therapy for anemia is discussed in articles describing the different causes of anemia (see Differential Diagnoses).

Follow-upFurther Outpatient Care

Patients with chronic anemia can usually be cared for on an outpatient basis. Follow-up care is necessary to ensure that therapy is being continued and to assess the efficacy of treatment.

Transfer

Patients with a benign etiology for anemia usually do not require transfer to another institution.

Occasionally, transfer is necessary to establish the etiology of the anemia or to provide a treatment that is not locally available.

If patients are being transferred for diagnostic reasons, transferring them before transfusion is helpful. If the transfusion is necessary before transfer to achieve hematopoietic stability, consult with the receiving physician to determine laboratory tests that should be performed before transfusion.

Patients who are hemodynamically unstable should not be transported.

Complications

The most serious complications of severe anemia arise from tissue hypoxia. Shock, hypotension, or coronary and pulmonary insufficiency can occur. This is more common in older individuals with underlying pulmonary and cardiovascular disease.

Hemolytic transfusion reactions and transmission of infectious disease are risks of blood product transfusions. Patients with autoimmune antibodies against RBCs are at greater risk of a hemolytic transfusion reaction because of difficulty in cross-matching the blood.

Occasionally, the blood of patients with autoimmune hemolytic anemia cannot be cross-matched in vitro. These patients require in vivo cross-matching in which incompatible blood is transfused slowly, and periodic determinations are made to ensure the patient is not developing hemoglobinemia. This method should only be used in patients with either significant hypoxia from the anemia or evidence of coronary insufficiency.

Prognosis

Usually, the prognosis depends on the underlying cause of the anemia. However, the severity of the anemia and the rapidity with which it developed can play a significant role. Similarly, the age of the patient and the existence of other comorbid conditions influence outcome.

Patient Education

Inform patients of the etiology of their anemia, the significance of their medical condition, and the therapeutic options available for treatment.

Because no effective specific treatment of the underlying disease exists, educate patients requiring periodic transfusions about the symptoms that

herald the need for transfusion. Likewise, they should be aware of the potential complications of transfusion.

MiscellaneousMedicolegal Pitfalls

Negligence in transfusion of either incompatible blood or blood containing a potentially identifiable infectious agent

Failure to recognize a hemolytic transfusion reaction and to initiate prompt and appropriate therapy

Delayed diagnosis, investigation, and treatment of a neoplastic disorder because the etiology of an anemia was not pursued in a timely manner

Failure to provide appropriate therapy and to ensure that the patient has adequate follow-up care

Underestimating the potential severity of an anemia (This usually occurs in patients who are bleeding or have an autoimmune hemolytic anemia.)

Multimedia

Media file 1: Anemia. Decreased production of red blood cells is suggested in certain patients with anemia. Bone marrow biopsy specimen allows categorization of patients with anemia without evidence of blood loss or hemolysis into 3 groups: aplastic or hypoplastic disorder, hyperplastic disorder, or infiltration disorder. Each category and its associated causes are listed in this image.

Anemia in Elderly PersonsAndrew S Artz, MD, Assistant Professor, Department of Medicine, Section of Hematology/Oncology, The University of Chicago Pritzker School of MedicineWilliam B Ershler, MD, Deputy Clinical Director and Senior Investigator, Clinical

Research Branch National Institute on Aging, National Institute of Health; Director, Institute for Advanced Studies in Aging and Geriatric Medicine; Clinical Professor of Medicine, George Washington University College of Medicine

Updated: Sep 29, 2009

IntroductionBackground

Anemia is an important sign that often points to a serious and possibly treatable medical condition. Although defined as a reduction in red blood cell (RBC) mass, other readily available measures that estimate RBC mass such as hemoglobin (Hb) concentration and hematocrit (Hct) are commonly used.

In elderly persons (defined as those older than 65 y for the purpose of this article), the etiology of anemia differs sufficiently from younger adults to warrant considering anemia in elderly persons as a distinct entity.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

Pathophysiology

Hematopoiesis, the production of blood elements, occurs in an orderly, hierarchical fashion. Blood cell production requires stem cells, a functioning bone marrow microenvironment, nutrients, and cytokines. A pluripotent hematopoietic stem cell gives rise to committed progenitors of myeloid, erythroid, and megakaryocytic lineages.

Erythropoiesis specifically relates to the arm of hematopoiesis that generates erythrocytes. The earliest committed erythroid lineage progenitors include the BFU-E (burst-forming unit-erythroid), which later give rise to CFU-E (colony-forming unit-erythroid). Normal erythropoiesis in adults occurs exclusively in the bone marrow and is generally restricted to the pelvis, vertebrae, sternum, ribs, and proximal femurs.

Erythropoietin physiology

Various hematopoietic growth factors support stem cell proliferation, differentiation, and survival. Erythropoietin (EPO), a glycoprotein hematopoietic

growth factor, serves as a primary regulation of RBC production.[1,2 ]Synthesis and EPO regulation occurs primarily in the kidney with a smaller contribution by liver hepatocytes.[3,4,5,6,7 ]As a consequence, renal failure inexorably leads to anemia from impaired EPO production.

Reduced tissue oxygenation (rather than diminished RBC production), typically from anemia or hypoxia, potently stimulates a logarithmic enhancement of EPO synthesis.[8 ]Elevated serum EPO levels enhance erythrocyte production primarily by inhibiting apoptosis of erythroid progenitor cells and to a lesser degree by enhancing erythroid progenitor proliferation and differentiation.[9 ]

The reticulocyte, an early RBC that has lost the nucleus but retained the polyribosomal reticular network, eventually emerges into the blood. After 1-4 days, reticulocytes lose this ribosomal network and mature into RBCs. Mature RBCS have an average life span in the blood of 100-120 days. Macrophages engulf senescent RBCs in the spleen, liver, and marrow.

Erythropoiesis with aging

Basal erythropoiesis and RBC mass in aged mice appears similar to younger mice, although the measured Hct may be slightly lower secondary to dilution.[10,11 ]In response to stress, such as hypoxia, bleeding, or environmental perturbation, aged mice have an impaired erythropoietic response compared with younger mice.[10,12,13 ]

Estimates of RBC mass

RBCs are largely composed of Hb, which is a complex molecule essential in delivering oxygen from the lungs to the tissues. Hb contains a heme-iron complex, and each RBC has hundreds of millions of Hb molecules. Thus, the RBCs serve as the largest storage compartment of iron in the body, and RBC loss often leads to iron deficiency.

Frequency

United States

In the vast majority of patients, Hb represents an excellent and easily reproducible measure of RBC mass. The Hb value below which anemia is defined varies. The World Health Organization (WHO) Hb thresholds of less than 13 g/dL for men and less than 12 g/dL for women are the most common definitions used for anemia in the elderly.[14 ]The threshold has been widely criticized based upon an association of

adverse outcomes with higher Hb concentrations.[15,16 ]The WHO criteria remain useful to compare anemia prevalence in different studies.

Hb thresholds for anemia may be defined distinctly for various reasons; thus, different thresholds are considered:

1. Prognostic marker: Numerous studies have shown that mildly low Hb values, often 1 - 2 g/dL above the WHO threshold, have been associated with increased mortality, hospitalization, and functional decline in elderly persons.

2. Etiologic marker: Clinicians most often define anemia to determine if an etiologic evaluation should be pursued. A wealth of data shows that important causes are uncovered if an evaluation is performed for anemia as defined by the WHO threshold.

3. Treatment: A lower Hb threshold is often used when deciding whether to treat with pharmacologic erythropoietin or RBC transfusions.

In addition to the varying thresholds for anemia, the highly heterogeneous nature of the elderly population has lead to multiple estimates of anemia prevalence in the elderly. One estimate suggests that more than 3 million elderly Americans are anemic.[17 ]

Table 1. Anemia Prevalence in the Elderly Based on WHO Criteria

Study Age Population PrevalenceGuralnik et al, 2004[ 17 ]

≥65 y Community-dwelling elderly, American

10.6%

Ferrucci et al, 2007[ 18 ]

≥65 y Community-dwelling elderly, Italian

11%

Denny et al, 2007[ 19 ]

≥71 y Community-dwelling

24%

Joosten et al, 1992[ 20 ]

≥65 y Hospitalized 24% (defined as Hb <11.5 g/dL)

Artz et al, 2004[ 21 ] Most ≥65 y Nursing home 48%

International

Studies from Europe and Japan[22 ]indicate a fairly similar prevalence of anemia in elderly adults as in the United States. Prevalence estimates of anemia in elderly persons living in developing countries are lacking.

Mortality/Morbidity

Morbidity and mortality related to anemia in the elderly can occur both from the underlying disease related to the anemia and the adverse effects of anemia itself. Multiple epidemiologic studies show an association between anemia or even mildly low Hb above the WHO threshold for anemia (ie, <14 g/dL) and a worse outcome, including the following:

Increased mortality[16,19,23,24,25,26,27 ]

Increased hospitalization[16,25,28 ]

Increased difficulty with mobility[26,29 ]

Falls[30,31 ]

Decreased activities of daily living and instrumental activities of daily living[19 ]

The presence of other conditions (cardiovascular disease) appears to increase the negative prognostic impact on survival

den Elzen et al examined the effect of anemia and comorbidity on functional status and mortality in old age in the Leiden 85-plus Study, a Dutch population-based prospective follow-up study of 562 people aged 85 years.[32 ]Over 5 years of annual follow-up, the 26.7% of study participants who had anemia at baseline had more disability in activities of daily living, worse cognitive function, and more depressive symptoms than participants without anemia at baseline (P ≤ 0.01).

Although these differences disappeared after adjustment for comorbidity, a greater increase in disability in instrumental activities of daily living remained; also, incident anemia during follow-up was associated with an additional increase in disability in basic activities of daily living.[32 ]Prevalent and incident anemia were both associated with an increased risk of death (hazard ratio [HR] for prevalent anemia 1.41, 95% confidence interval [CI] 1.13-1.76; HR for incident anemia 2.08, 95% CI 1.60-2.70).

Race

Anemia is approximately 3 times more prevalent in elderly blacks than among non-Hispanic whites.

Older Mexican Americans have a fairly similar prevalence to that of elderly whites. The median Hb for elderly blacks is approximately 0.8 g/dL lower than for whites.[19,26 ]

The cause for the higher prevalence in blacks has not been established. However, some of the disparity is likely related to biologic differences. Anemia is more common in black children,[33 ]and Hb appears to decline similarly with advancing age in blacks and whites.[19 ]In younger adults, part of the increased anemia prevalence relates to an alpha-thalassemia trait.[34 ]

Whether anemia has different adverse consequences in blacks is unclear.[19,26 ]

Sex

Anemia in elderly persons is more common in men than in women. Some of the difference stems from employing a lower Hb threshold (eg, Hb <12 g/dL) for women than for men (ie, <13 g/dL). 

Age

Hb declines slightly, and anemia prevalence rises in both men and women with advancing age.[8 ]This change is more pronounced in men.

Among community-dwelling adults aged 65 years and older, one study showed anemia prevalence was 8% among those aged 65-74 years, 13% for those aged 75-84 years, and 23% for those aged 85 years and older.[17 ]

The reason for increased anemia prevalence with advancing age has not been established.

ClinicalHistory

A comprehensive history, physical examination, and laboratory evaluation are required for an elderly person found to have anemia. As a laboratory finding, anemia is often recognized incidentally after the initial evaluation. The multiple causes for anemia in elderly persons and the influence of anemia and anemia treatment on the pathogenesis of associated conditions justify a complete anemia evaluation rather then a piecemeal approach.

Previous blood counts:   Previous blood counts represent one of the most underused and invaluable tools to help clinicians determine the acuity of the anemia. The causes for an acute fall in Hb are narrow (eg, bleeding, hemolysis) as opposed to the more common slow decline over time. Elderly persons have frequently had previous blood counts that are easily retrievable.

Transfusion history: One should inquire whether RBC transfusions have previously been administered. A history of transfusions will alert the clinician to a chronic problem.

Medical history: Recent hospitalization often results in anemia, particularly in elderly persons. The anemia is often the consequence of multiple phlebotomies as well as the acute illness itself. Thus, the prehospitalization Hb can be invaluable.

o Recent surgery suggests blood loss and necessitates comparison to preoperative Hb values. When surgery requires RBC transfusion, the patient has often had a preexisting low Hb before the surgery, had another condition preventing an appropriate response to blood loss, or both.

o Diseases that frequently cause anemia should be noted, including myelodysplasia, cancer, and cancer chemotherapy (especially myelosuppressive chemotherapy), chronic kidney disease, and rheumatologic disorders.

o End-stage renal disease (ESRD) uniformly causes anemia, unless an erythropoietin-stimulating agent is administered.

o Conditions that are associated with specific types of anemia should be clearly identified.

Lymphoproliferative and autoimmune disease may cause autoimmune hemolytic anemia.

Previous chemotherapy or radiotherapy raises the possibility of therapy-related myelodysplastic syndrome.

Alcohol overuse may go unrecognized in the elderly and leads to deficiencies of vitamin B-12, folate, marrow hypoproliferation, and gastrointestinal bleeding.

Racial backgroundo Family history can be useful for considering a coexistent thalassemia trait or other

hemoglobinopathy.o Ancestry should be considered, with recognition that blacks may have an

approximately 0.8 g/dL lower Hb than whites. Symptoms: Symptoms relate to the rapidity of the anemia, the depth of the Hb fall, and

concomitant medical conditions. The nonspecific nature of anemia-related symptoms poses a major challenge. Nevertheless, a detailed history often identifies the presence of anemia-related symptoms. Inquiring about specific tasks, such as walking up stairs, that lend additional objective information is often useful. Patients may mistakenly attribute decreased energy to aging or other medications.

o Special attention should be paid to elements that indicate a cause for the anemia (eg, presence or symptoms of cancer, gastrointestinal blood loss, infection, arthritis) and symptoms related to anemia (fatigue, shortness of breath, tinnitus).

o Most symptoms of anemia are nonspecific; however, a temporal relation between falling Hb and symptom exacerbation is very useful. Blood loss should be directly inquired about (eg, melena, hematuria, hemoptysis, hematemesis).

o General symptoms Fatigue Weakness Dyspnea on exertion Tinnitus Presyncope Palpitations Headache Poor concentration Pale skin

o Specific causes and associated signs and symptoms of anemia

Iron deficiency Blood loss (tarry stools, red blood in the stools, hematuria) Pica (desire to consume unusual substances such as ice or dirt) Koilonychia (spoon-shaped changes in the nail beds) Dysphagia (from esophageal webs) Mouth and tongue soreness (from atrophy)

Vitamin B-12 deficiency Neuropathy Ataxia Dementia

Hemolysis Jaundice Dark urine (if intravascular hemolysis)

Physical

The physical examination may uncover an anemia etiology, signs related to the anemia, or both. Thus, the examination must be comprehensive. Special attention should be paid to the following:

Pallor Icterus Lymphadenopathy Tachycardia Cardiac murmurs Hepatomegaly Splenomegaly Edema Stool for color Stool test for blood

Causes

Multiple conditions can lead to anemia in elderly persons. Moreover, the anemia may be multifactorial. Nevertheless, in the majority of cases of anemia in elderly persons, an etiology can be found. The most common causes include iron deficiency (with or without blood loss), chronic disease/inflammation and chronic kidney disease.[ 17 ][ 20, 21, 35 ]

Other etiologies of anemia in the elderly include deficiencies of folate or vitamin B-12, diseases of the bone marrow (eg, myelodysplastic syndromes, aplastic anemia, paroxysmal nocturnal hemoglobinuria, myeloproliferative syndromes, acute or chronic leukemia, lymphoma), hypothyroidism, hypersplenism, and hemolytic anemia. Despite a complete

evaluation, a significant minority of cases have no etiology uncovered (ie, unexplained anemia).[ 20, 21 ]

Table 2. Prevalence of Various Etiologies of Anemia in Elderly Persons

Cause PrevalenceIron deficiency 15-23%Chronic disease/inflammation 15-35%Chronic kidney disease 8%Endocrinopathies <5%Vitamin B-12 or folate deficiency

0-14%

Myelodysplastic syndromes 0-5%Unexplained 17-45%

Iron-deficiency anemia

Identifying iron-deficiency anemia in elderly persons is essential and can be corrected. More importantly, iron deficiency, particularly in elderly persons, often points to an underlying gastrointestinal pathology, including malignancy.[36,37 ]Despite the importance of establishing a diagnosis, iron-deficiency anemia represents only 15-23% of cases of anemia among the elderly.[17,20,21 ]

Anemia of chronic disease and inflammation

Anemia of chronic disease appears to be primarily related to inflammation, thus leading to the term anemia of chronic inflammation.[38 ]Anemia of chronic inflammation is a hypoproliferative anemia characterized by low serum iron and adequate to increased iron stores.[39 ]Inflammatory markers implicated in anemia of chronic inflammation include tumor necrosis factor alpha (TNF-alpha),[40,41 ]interleukin-1 (IL-1),[42,43 ]interferon gamma (IFN-gamma),[44 ]and IL-6.[45,46 ]Inflammation inhibits erythropoiesis through a variety of mechanisms.[47 ]

The discovery of hepcidin has considerably clarified the pathophysiology of anemia of chronic inflammation. Hepcidin is a hepatically synthesized 25 amino acid peptide that serves as a primary regulator of iron homeostasis. Hepcidin directly inhibits ferroportin, a protein that transports iron out of cells that store it. Inflammation, particularly with IL-6, increases hepcidin expression.

Anemia of chronic inflammation and the disordered iron homeostasis that is typically found may be explained by increased hepcidin expression.[48,49 ]Hepcidin testing is not clinically available and has not been validated as a diagnostic test for anemia of chronic inflammation. No established diagnostic criteria for anemia of chronic inflammation exist. In epidemiologic studies, low serum iron (eg, <60 μg/dL) with or without low to normal transferrin have been used.[17 ]

An alternative method is to consider anemia of chronic inflammation to exist when the patient has an inflammatory comorbid condition.[21 ]Not all conditions or even conditions leading to anemia warrant a diagnosis of anemia of chronic inflammation. For example, anemia due to renal insufficiency or endocrine dysfunction is not considered anemia of chronic inflammation.[39 ]Thus, diseases such as hypertension and osteoarthritis should not lead directly to anemia.

Comorbid diseases often contribute indirectly to anemia of chronic inflammation. Nonsteroidal drugs for osteoarthritis may lead to gastrointestinal bleeding and iron deficiency, whereas hypertension may cause anemia from chronic kidney disease. Case reports have proposed that anemia of chronic inflammation may exist in elderly persons absent a chronic condition.[50 ]This entity, known as “primary defective iron-reutilization syndrome” may respond to hormonal therapy.[51 ]

Renal insufficiency

Chronic kidney disease is an important cause of anemia in elderly persons, especially considering that renal function declines with aging.[52,53 ]Reduced renal EPO production is the primary factor leading to anemia in chronic kidney disease. Serum EPO levels have been shown to be inappropriately low at a creatinine clearance of less than 40 mL/min.[54,55 ]The precise degree of renal dysfunction sufficient to cause anemia remains controversial. Mild Hb decreases in adults may be detected at a creatinine clearance of 40-60 mL/min.[56,57 ]

A study among community-dwelling elderly persons suggested anemia and low EPO levels are independent of age and other factors at a creatinine clearance less than 30 mL/min.[58 ]We also examined renal function in older residents in a skilled nursing facility.[59 ]Forty-three percent had chronic kidney disease (defined as a creatinine clearance less than 60 mL/min). Chronic kidney disease increased the risk of anemia.

Nutrient deficiencies

Low vitamin B-12 levels in elderly persons are not uncommon. However, vitamin B-12 deficiency is a very uncommon cause of anemia in elderly persons.[60 ]Folate deficiency is also uncommon, in part related to widespread vitamin supplementation.[61 ]To the extent such mineral deficiencies are reversible and suggest other conditions (eg, pernicious anemia or hemolysis, respectively), they remain important to identify.

Myelodysplastic syndromes

Myelodysplastic syndromes represent a heterogeneous group of disorders characterized by clonal hematopoiesis and peripheral blood cytopenias. They are more common in older adults and may present as an isolated anemia. In the elderly, anemia in conjunction with macrocytosis, thrombocytopenia, or neutropenia absent another cause raises the suspicion of myelodysplastic syndrome.[62,63 ]Alternatively, Myelodysplastic syndrome is an unlikely cause of idiopathic normocytic anemia in elderly persons.[64,65,66 ]When evaluating mean corpuscular volume (MCV), one must be cognizant that recent RBC transfusions will alter the values. Thus, retrieving hematology values before a transfusion is critical.

Other miscellaneous primary hematologic disorders

A variety of other primary hematologic disorders have anemia as a manifestation. Thrombotic thrombocytopenic purpura (TTP), although rare, should be considered in every patient with anemia, as this a medical emergency requiring prompt intervention. Often (but not always), patients will have other cardinal features of the disease, including thrombocytopenia, altered mental status, and renal insufficiency.

Elderly patients with acute leukemia can have a more smoldering disease course than younger patients. These patients may present with a low, high, or even normal white blood cell (WBC), although in most individuals the WBC differential is abnormal. This fact emphasizes the importance of performing a manual differential in all patients with an abnormal complete blood cell (CBC) count.

Chronic lymphocytic leukemia (CLL) is common in elderly persons. Although most patients will have either an elevated WBC or lymphadenopathy at presentation, some patients will present with autoimmune hemolytic anemia and could have relatively little evidence of CLL. Multiple myeloma should always be considered,

particularly in patients with elevated globulin levels. Patients with aplastic anemia will have a low WBC and/or platelet count. Patients with myeloproliferative diseases often have an elevated WBC; however, some patients with myelofibrosis will have anemia as the prominent abnormality.

Finally, anemia can be a sign of bone marrow infiltration from lymphoma. Not uncommonly the patient will not have palpable lymphadenopathy, but computed tomography (CT) scans could reveal extensive internal lymphadenopathy. In these patients, measurement of an lactate dehydrogenase (LDH) level is essential.

Thyroid disease

Hypothyroidism reduces RBC mass and may lead to a normocytic anemia.[67 ]Occasionally, hypothyroidism may lead to macrocytosis without anemia.[68 ]Hypothyroidism and hyperthyroidism may be associated with pernicious anemia,[69 ]and both conditions may also lead to a correctable anemia, but most patients with thyroid abnormalities are not anemic.[69,70 ]The degree of thyroid dysfunction leading to anemia remains unknown. Generally, the more severe the thyroid dysfunction, the more likely anemia will occur. A therapeutic trial correcting the thyroid abnormalities may be necessary to definitively determine their role in causing lower Hb concentration.

Unexplained anemia in the elderly

The traditional notion has been that anemia in the elderly always reflects a serious underlying condition.[71 ]However, it has long been recognized that a proportion of patients, usually older, have anemia that does not meet diagnostic criteria for a specific etiology (unexplained anemia). Multiple studies of anemia in elderly persons over the past 30 years have confirmed that unexplained anemia represents a considerable proportion of cases of anemia in elderly persons, ranging from 15-45%.[5,17,20,21,35,72,73,74 ]Even with the advent of better tests such as serum ferritin, methylmalonic acid, soluble transferrin receptor, a significant portion of elderly persons with anemia will be diagnosed as having unexplained anemia.[21 ]

Unexplained anemia is generally a condition of elderly persons. It appears more commonly with advancing age and is rarely, if ever, encountered in younger adults.[75 ]In a longitudinal study in healthy elderly subjects, Hb slowly but predictably declined with aging.[8 ]In elderly patients who reside in nursing homes, we found a very high prevalence of unexplained anemia (45%).[21 ]

Whether unexplained anemia represents a spectrum of undiagnosed etiologies or has a unifying pathogenesis remains unclear. The present data support unexplained anemia as distinct from anemia of chronic inflammation. Guralnik and colleagues evaluated data from community-dwelling elderly and defined anemia of chronic inflammation as a serum iron less than 60 μg/dL but without iron deficiency.[17 ]C-reactive protein (CRP) was elevated in 27% of patients who had anemia of chronic inflammation compared with only 9% in those with unexplained anemia.

In a nursing-home study categorizing anemia of chronic inflammation as the presence of an inflammatory comorbid condition, the mean CRP was 36.9 mg/dL for those with anemia of chronic inflammation compared with 6.0 mg/dL for patients with unexplained anemia. IL-6 levels were significantly higher in cases of anemia of chronic inflammation (44.3 pg/mL +/– 72.4) compared with cases of unexplained anemia (8.5 pg/mL +/– 7.8).

Thus, anemia of chronic inflammation as diagnosed by criteria that differed in 2 studies showed higher markers of inflammation for anemia of chronic inflammation relative to unexplained anemia. Although higher inflammatory markers have not been used as the sole criterion for the diagnosis of anemia of chronic inflammation, the presence of significant inflammation (ie, high CRP) should alert the clinician to a possible inflammatory component. The expected inflammatory profile may be blunted, however, when patients are undergoing treatment for a chronic inflammatory disease.

Another concern has been that unexplained anemia reflects occult myelodysplastic syndrome.[17,76 ]In the National Health and Nutrition Examination Survey III (NHANES III) study of anemia in the elderly, 17% of cases of unexplained anemia had hematologic abnormalities that may have been consistent with myelodysplastic syndrome.[17 ]These included an MCV greater than 100 fL, a leukocyte count less than 3 K/uL, or platelet count less than 150 K/uL. In a nursing home study, 27 patients exhibited a normocytic unexplained anemia, whereas 3 patients had an unexplained macrocytic anemia (ie, 3 of 30 patients or 10% with unexplained anemia).[21 ]

Relative EPO deficiency

In the prototypical model of complete renal failure, inadequate endogenous EPO secretion rather than a primary marrow problem leads to anemia.[55 ]Even in renal conditions without overt renal glomerular filtration abnormalities, endocrine

function as measured by the endogenous EPO response to anemia may be impaired. For example, children with nephritic syndrome, before significant renal clearance impairment, have a blunted endogenous EPO response to anemia.[77 ]A similar blunted EPO response occurs in patients with diabetes independent of reduced glomerular filtration.[78 ]Finally, administration of angiotensin-converting enzyme (ACE) medication may suppress EPO secretion and precipitate anemia.[79,80 ]

In older adults with preserved renal function, the endogenous EPO response in those having renal-damaging conditions (ie, diabetes and hypertension) is blunted relative to those not having such a condition.[8 ]A decline in renal function may be a feature of aging that is accentuated by hypertension and diabetes.[81 ]Thus, a relative EPO deficiency, potentially from early renal damage, likely contributes to unexplained anemia.[8,21,58 ]

Sex hormones

The general Hb difference between men and women relates in large part to the erythropoietic effects of testosterone, which can be illustrated by the fact that after orchiectomy or androgen deprivation therapy for prostate cancer, Hb falls by 1.2 g/dL to 1.5 g/dL on average.[82,83 ]Further, testosterone replacement raises Hb in older men.[84 ]

Testosterone declines with aging in men.[85 ]The greater rate of Hb decline in men than in women with advancing age raises the suspicion that falling testosterone may cause unexplained anemia.[8,86 ]A large epidemiologic study showed that men with lower testosterone were more likely to have anemia. However, one small study did not show a difference in testosterone between anemic and nonanemic older men,[64 ]and the proportion of unexplained anemia appeared similar in men and women.[17

]

Differential DiagnosesOther Problems to Be Considered

Acute lymphoblastic leukemia Acute myelogenous leukemia Anemia of chronic inflammation / anemia of chronic disease from infection, malignancy,

or rheumatologic disease Anemia of chronic renal insufficiency Aplastic anemia

Blood loss Chronic lymphocytic leukemia Chronic myelogenous leukemia Folic acid deficiency Hairy cell leukemia Hemolytic anemia Hyperthyroidism Hypothyroidism Iron-deficiency anemia Lymphoma Medications Multiple Myeloma Myelodysplastic syndromes Myeloproliferative syndromes Neoplasia (nonhematologic) Paroxysmal nocturnal hemoglobinuria Pernicious anemia Splenomegaly Thalassemia trait Thrombotic thrombocytopenic purpura Unexplained anemia of the elderly Vitamin B-12 deficiency

WorkupLaboratory Studies

Numerous algorithms have been proposed for the evaluation of anemia and anemia in elderly persons. They are often based upon kinetic measures by first assessing the reticulocyte count, RBC size using the MCV, or peripheral smear. Such an investigation must account for the unique epidemiology in this population.

Several common facts guide the evaluation:

Most anemia in elderly persons is hypoproliferative (ie, reticulocytosis is inadequately low).

Generally, the more severe the anemia, the more likely an obvious and/or serious cause will be detected.

Previous blood counts are often available. Approximately one third of older subjects will have an unexplained anemia, where no

proximate cause can be identified. Direct examination of the peripheral smear is often unavailable or difficult to interpret.

Anemia can be multifactorial.

Initiate an evaluation under the following conditions:

Hb below the WHO threshold (Hb <13 g/dL for men; <12 g/dL for women) Hb that has fallen >2 g/dL over any period without an adequate explanation (eg, major

surgery) Hb that does not recover to baseline after an acute event Falling Hb and symptoms that may be related to anemia

Should the anemia etiology not be apparent from the initial history and physical examination, a comprehensive evaluation is useful.

Recommended studies include the following:

CBC counto WBC differentialo Platelet counto RBC parameters (MCV)

Examination of peripheral blood smear Reticulocyte count LDH Serum ferritin Serum iron Total iron-binding capacity Vitamin B-12 Folate Thyroid-stimulating hormone Serum creatinine and estimated glomerular filtration rate Serum protein electrophoresis, especially if total globulins are elevated

In about two thirds of elderly persons with anemia, this initial evaluation will lead to a presumed etiology for the anemia. A reiterative process is essential. Once a deficiency is identified, the blood counts should be reevaluated after identifying the problem, correcting the deficiency, or both.

Other tests often performed include the following:

CRP Serum EPO Hepatic transaminases Urine immunoelectrophoresis

Additional studies to be performed as indicated include the following:

Possible iron deficiencyo Fecal occult blood testo Urine analysis for bloodo Soluble transferrin receptoro Bone marrow aspirate with iron staino Colonoscopyo Esophagogastroduodenoscopyo Small bowel studyo Urine hemosiderino Anti-tissue transglutaminase antibodies

Possible hemolysiso Indirect bilirubin and direct bilirubino Serum haptoglobino Direct and indirect Coombs testso Urine Hbo Urine hemosiderino Splenic ultrasound

Androgen insufficiencyo Testosterone level

Some additional points on diagnostic testing are discussed below.

Iron deficiency

Iron deficiency occurs in approximately 20% of elderly anemic patients. Because iron deficiency is correctable and often reflects gastrointestinal pathology including malignancy, every elderly anemic adult requires a thorough evaluation to determine the underlying cause of iron deficiency.

Numerous tests are available to diagnose iron deficiency, including RBC MCV, serum iron, serum transferrin, iron saturation, serum ferritin, soluble transferrin receptor (sTFR), reticulocyte Hb content, erythrocyte protoporphyrin, and bone marrow examination. Serum ferritin is the most useful test for diagnosing iron-deficiency anemia. Low serum ferritin (eg, <12 ng/mL) is highly specific for iron-deficiency anemia.[87 ]

As an acute phase reactant, ferritin can be elevated in inflammation, complicating the diagnosis of iron-deficiency anemia in the presence of inflammation.[88 ]Intermediate ferritin values between 18 and 44 ng/mL are highly suggestive of

iron deficiency in the elderly,[89,90 ]and ferritin values above 100 ng/dL make iron deficiency highly unlikely.[90 ]Thus, raising the threshold for serum ferritin in the elderly to account for increased inflammation related to aging and/or comorbid conditions enables reasonable sensitivity and specificity for iron-deficiency anemia.

A major pitfall is misinterpreting the MCV. Although microcytosis occurs in iron-deficiency anemia, microcytosis is a late finding and typically occurs only after chronic iron deficiency, leading to a Hb value less than 10 g/dL. Further, the MCV is an average of all the RBCs analyzed. The impact of other factors may abrogate the standard changes in cell size. For example, alcohol use or liver disease leads to increased RBC size. That said, a developing microcytic anemia in an older adult absent an obvious chronic inflammatory disease is highly suspicious for iron deficiency (eg, an initial MCV of 85 and Hb of 12 g/dL changes to an MCV of 75 and Hb of 9.5 g/dL).

Alternative strategies to diagnose iron-deficiency anemia have been studied, most commonly employing the sTFR. The sTFR is a truncated fragment of the membrane receptor that is increased in iron deficiency, when the iron availability for erythropoiesis is low. STFR enhances diagnostic sensitivity in elderly persons compared with using a very low serum ferritin for iron-deficiency anemia.[91 ]Another method standardizes sTFR based upon the serum ferritin. By using the log of the sTFR/ferritin, a ratio greater than 2.5 may indicate iron deficiency.

However, raising the threshold of ferritin to less than 30-50 ng/mL affords a similar or better diagnostic performance.[90,92 ]Further, sTFR is less sensitive in detecting early iron deficiency compared with ferritin.[93 ]The lack of laboratory standardization in reporting or a standardized value that is diagnostic of iron deficiency further complicates the use of sTFR.

Bone marrow evaluation has been considered the criterion standard for iron deficiency. In addition to cost and inconvenience, bone marrow examinations can be highly misleading and may require up to 7-9 aspirate smears to confidently prove iron stores are absent.[94,95 ]Thus, serum ferritin remains the standard test to exclude iron deficiency in the elderly.

Many older adults are subject to unnecessary endoscopic procedures for anemia. Unless acute bleeding is occurring, gastrointestinal bleeding causes anemia through iron deficiency. Thus, if iron stores are adequate and the anemia persists, an endoscopic evaluation will rarely, if ever, identify the cause of the anemia in elderly persons. Alternatively, should iron deficiency be suspected, a thorough endoscopic

evaluation is often necessary rather than only prescribing iron replacement. Occasionally the patient is too ill or the family does not desire an evaluation. Once must be careful not to judge the patient’s wishes, and clinicians should approach the patient and family with the options.

Vitamin B-12 and folate deficiencies

Vitamin B-12 and folate deficiencies are uncommon but essential to exclude as causes of anemia as these conditions are treatable and usually highlight the presence of another condition. For example, pernicious anemia should be considered in patients with vitamin B-12 deficiency. Folate deficiency has become very uncommon with routine supplementation.

Low vitamin B-12 levels are frequent in older adults. If a level of less than 200 pg/mL is detected, then etiologies of vitamin B-12 deficiency (eg, pernicious anemia, malabsorption) should be investigated and vitamin B-12 replenished. For equivocal levels of vitamin B-12, such as a level between 200 and 350 pg/mL, evaluate methylmalonic acid. An elevated methylmalonic acid level is evidence of a vitamin B-12 tissue deficiency. One must recognize that methylmalonic acid is elevated in renal dysfunction.

Homocysteine is elevated in vitamin B-12 deficiency and folate deficiency. If the methylmalonic acid is elevated in the setting of anemia and a low vitamin B-12, evaluate for vitamin B-12 deficiency and empirically treat the patient. Reevaluating the anemia after treatment is essential. Commonly, the anemia does not correct, which indicates that the low nutrient level was not causative. Anemia due to vitamin B-12 of folate deficiency need not be macrocytic. However, the presence of an MCV greater than 115 fL is highly suspicious for the megaloblastoid anemia that is seen with these deficiencies.

Unexplained anemia

Increasingly, it has become recognized that approximately one third of older adults do not have an obviously discernible cause of anemia upon an extensive evaluation. This anemia is generally mild (Hb from 9 to 12 g/dL, normocytic, and hypoproliferative [low reticulocyte count]). Potential explanations for this have included low testosterone, occult inflammation, reduced hematopoietic reserve with advancing age, inappropriately low serum EPO level, and myelodysplastic syndromes. It is clear that this anemia is typically associated with a low serum EPO level for the degree of anemia. The EPO level usually falls within the normal

reference range. However, this finding is abnormal, because serum EPO should rise with declining Hb values. The diagnosis of unexplained anemia assumes the clinician has excluded serious causes.

The threshold to pursue a bone marrow examination to exclude myelodysplastic syndromes remains unknown. However, the authors advocate considering a bone marrow examination in all patients who required RBC transfusion who otherwise have an unexplained anemia. Macrocytosis, thrombocytopenia, neutropenia, splenomegaly, or unexplained constitutional symptoms of fever, chills, early satiety, bone pain, or weight loss should prompt consideration of a bone marrow examination.

Macrocytic anemia

Macrocytic anemia in older adults truly demands a thoughtful investigation of potential causes as this more often reflects other conditions or bone marrow pathology. Laboratory MCV normal ranges vary. An MCV greater than 95-100 fL defines macrocytosis. The authors use an MCV of 100 fL or greater or an MCV of 95 or greater but rising more than 5 fL from previous counts.

Potential causes for macrocytic anemia include the following:

Vitamin B-12 deficiency Folate deficiency Medications (myelosuppressive chemotherapy, hydroxyurea, trimethoprim,

anticonvulsants) Alcohol overuse Liver disease Hypothyroidism Chronic obstructive pulmonary disease Reticulocytosis Spurious (eg, hyperglycemia or cold agglutinin disease) Marrow disease, especially myelodysplastic syndromes Cold agglutinin disease

Peripheral smear

A peripheral blood smear is invaluable, especially when determining if a primary bone marrow process accounts for macrocytic anemia. This generally requires a hematology or pathology review, rather than a technician-reported analysis of the peripheral smear. If no cause is identified, a hematology referral and/or bone

marrow examination should be considered. The more severe the anemia and the more severe the macrocytosis, the more likely a specific cause will be identified.

Imaging Studies

An ultrasound of the left upper quadrant could be helpful if the patient's body habitus makes examination for splenomegaly difficult 

Other Tests

A bone marrow aspirate and biopsy are used when a primary marrow disease (eg, MDS, aplastic anemia) is suspected. Occasionally, the marrow is used to accurately gauge iron stores, entertain marrow involvement of nonmarrow diseases (eg, infection, lymphoma), or consider nonmalignant marrow processes (eg, hemophagocytic syndrome, Gaucher disease). MDS should be diagnosed based on a bone marrow examination and not based only on the peripheral smear. Bone marrow examination generally has fewer complications and is less invasive than generally appreciated.

TreatmentMedical Care

The critical element is to identify reversible etiologies for the anemia (eg, iron deficiency, infection) and treat these appropriately. Iron deficiency, vitamin B-12 deficiency, and folate deficiency should be evaluated and treated in cases of anemia in elderly persons.

RBC transfusion

For severe anemia, RBC transfusion is warranted. Transfusions entail numerous and often underappreciated risks of infection, volume overload, transfusion reactions, and costs. Transfusing 2 units of RBCs may represent a considerable volume for elderly patients who have preexisting cardiac dysfunction. Repeated transfusions can result in iron overload and clinical manifestations of hemochromatosis. Recommendations for Hb thresholds below which RBC transfusions should be given vary from 5-10 g/dL.

The need for transfusion is also related to the rapidity of the Hb drop, as patients will be more symptomatic from a more acute drop in Hb. Because of concerns

about increased mortality when using a liberal transfusion policy, the authors generally restrict RBC transfusion to Hb levels that are less than 7-8 g/dL and are likely to continue to decline or to severe anemia symptoms.

Consultations

Consult a hematologist for bone marrow aspiration and biopsy. Consult a gastroenterologist for colonoscopy, esophagogastroduodenoscopy, or small

bowel evaluation.

Diet

Unless a deficiency has been identified as a cause of anemia in elderly persons, no specific dietary intervention will be fruitful.

Activity

Activity restrictions may be considered for symptomatic anemia in elderly patients who may have active cardiac symptoms until an appropriate cardiac evaluation has been performed.

MedicationMedications are used based upon the cause of the anemia in an elderly person. For unexplained anemia, no treatment has been well studied.

Erythropoiesis stimulating agents

Erythropoiesis-stimulating agents (ESAs) approved in the United States include epoetin-alfa (Procrit, Epogen) and darbepoetin-alfa (Aranesp). The primary indications are for anemia due to chronic kidney disease or cancer chemotherapy. Although ESA therapy has found widespread use for anemia due to chronic kidney disease (based on a 2006 Kidney Disease Outcomes Quality Initiative [KDOQI] consensus statement),[96 ]the risks and benefits in this population, particularly for older adults not on dialysis and not receiving RBC transfusions, remain unexplored.

In light of the increased risk of thrombosis, hypertension, and, potentially, progression of certain cancers associated with ESA use in a population at increased danger for such events, caution must be exercised. Prescribing of ESAs should be restricted to physicians experienced in the use and monitoring of such treatment.

The authors generally use an ESA for anemia due to chronic kidney disease to obviate RBC transfusions, assuming all other etiologies have been excluded. The authors will consider ESA therapy for anemia of chronic kidney disease if the Hb is less than 10 g/dL, the patient can be monitored closely for complications, the patient or caregiver understands the risks, and a clear quality-of-life improvement can be measured. The authors are careful not to exceed a Hb of 12 g/dL in light of the risk of increased complications at higher Hb concentrations.[97,98 ]Iron supplementation is frequently needed to prevent iron-restricted erythropoiesis once an elderly patient is on ESA treatment.

Mineral Supplements, Oral

Oral mineral supplements are used as supplements in situations of mineral deficiencies.

Ferrous Sulfate (Feosol; Fer-In-Sol, Fer-Iron; Feratab; Slow FE)

For iron-deficiency anemia, oral iron salts are the primary therapy. They should not be used for anemia in which there are adequate iron stores. Ferrous sulfate is inexpensive and readily available. Other iron salts may be employed. Gastrointestinal tolerance relates to the iron dosage rather than the formulation. Iron therapy should be continued for several months after repleting iron stores.

Dosing

Adult

320-325 mg (60-65 mg elemental iron) PO tid; taking this on an empty stomach enhances absorption, but it may increase gastrointestinal discomfort; if tolerance is problematic, reduce the dose to bid, take with food, and/or use a formulation that has less elemental iron

Pediatric

Not relevant

Interactions

Antacids may decrease the absorption; concurrent administration of iron may decrease the absorption of certain drugs (eg, quinolones, levodopa, methyldopa).

Some foods may decrease iron absorption, such as milk, cereal, fiber, coffee, tea, and eggs.

Concomitant oral ascorbic acid (vitamin C) enhances iron absorption.

Contraindications

Documented hypersensitivity, iron overload, anemia without low iron or inadequate stores

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Precautions must be taken if children could encounter iron tabs; this includes child-proof containers and storing out of the reach of children.

Gastrointestinal intolerance includes nausea, constipation, gastric erosion, and GI irritation.

Colony-stimulating Factors

Colony-stimulating factors are used to enhance erythropoiesis when endogenous EPO levels are low.

Epoetin alfa (Procrit, Epogen)

Erythropoietin-stimulating agents (ESAs) such as epoetin alfa are used to enhance erythropoiesis in conditions in which endogenous erythropoietin levels are inadequately low. They are not approved nor have they been rigorously studied in anemia in the elderly.

ESA use has been approved for anemia due to chronic renal failure, cancer chemotherapy, zidovudine-treatment for HIV, before surgery to reduce allogeneic RBC transfusions.

A black box warning has been issued for ESAs. Healthcare providers may access updated prescribing information from the FDA's Infopage.

Dosing

Adult

Varies by indication; epoetin alfa is given 1–3 times/wk SC/IM; IV administration is generally reserved for dialysis patients

Pediatric

Not relevant

Interactions

None reported

Contraindications

Documented hypersensitivity to erythropoietin, human albumin, mammalian cell-derived products or any component in the formulation; uncontrolled hypertension; active thrombosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

A black box United States FDA warning has been issued. ESAs may increase the risk of cardiovascular events, thromboembolic events, and increase mortality; hemoglobin targets >12 g/dL and a rapid rise may increase these risks; ESAs may increase the risk of seizures and exacerbation of porphyria; pure red cell aplasia due to neutralizing antibodies has been reported mostly in treatment for chronic renal

failure.

Neoplastic cell lines have been shown to express erythropoietin receptors, and there is a potential that ESAs may have increased time to progression in some cancer studies; iron stores should be adequate before starting therapy (ie, ferritin >100 mcg/mL or iron saturation 20%).

ESAs should only be used by healthcare providers experienced in their usage and monitoring. Hemoglobin/hematocrit, blood pressure, and iron stores must be monitored closely in patients on this therapy; strong consideration should be given to keep the hemoglobin <12 g/dL and minimize rapid rises of hemoglobin (>1 g/dL) over a 1-week period while the patient is on treatment.

Darbepoetin alfa (Aranesp)

Erythropoietin-stimulating agents (ESAs) such as darbepoetin alfa are used to enhance erythropoiesis in conditions in which endogenous erythropoietin levels are inadequately low. They are not approved nor have they been rigorously studied in anemia in the elderly.

ESA use has been approved for anemia due to chronic renal failure, cancer chemotherapy, zidovudine-treatment for HIV, before surgery to reduce allogeneic RBC transfusions.

A black box warning has been issued for ESAs. Healthcare providers may access updated prescribing information from the FDA's Infopage.

Dosing

Adult

Varies by indication; darbepoetin alfa is given 1–3 times/wk SC or IM; IV administration is generally reserved for dialysis patients

Pediatric

Not relevant

Interactions

None reported

Contraindications

Documented hypersensitivity to erythropoietin, human albumin, mammalian cell-derived products, or any component in the formulation; uncontrolled hypertension; active thrombosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

A black box United States FDA warning has been issued. ESAs may increase the risk of cardiovascular events, thromboembolic events, and increase mortality; hemoglobin targets >12 g/dL and a rapid rise may increase these risks; ESAs may increase the risk of seizures and exacerbation of porphyria; pure red cell aplasia due to neutralizing antibodies has been reported mostly in treatment for chronic renal failure.

Neoplastic cell lines have been shown to express erythropoietin receptors, and there is a potential that ESAs may have increased time to progression in some cancer studies; iron stores should be adequate before starting therapy (ie, ferritin >100 mcg/mL or iron saturation 20%).

ESAs should only be used by healthcare providers experienced in their usage and monitoring. Hemoglobin/hematocrit, blood pressure, and iron stores must be monitored closely in patients on this therapy; strong consideration should be given to keep the hemoglobin <12 g/dL and minimize rapid rises of hemoglobin (>1 g/dL) over a 1-week period while the patient is on treatment.

Follow-upPrognosis

Low Hb is a powerful prognostic marker for multiple adverse outcomes in the elderly. Clinicians should be alerted to the increased risk of morbidity, hospitalization, and mortality in cases of anemia in the elderly. Aside from addressing underlying etiologies or comorbid conditions, intervention to correct the anemia remains experimental.

Patient Education

It is invaluable for elderly patients with anemia to have documentation of their Hb concentration if it is low. Thus, if hospitalization occurs, their baseline Hb will be available.

MiscellaneousMedicolegal Pitfalls

Failure to recognize an immediately life-threatening condition such as TTP or acute leukemia

Not evaluating an elderly person with anemia and missing a treatable condition Not fully evaluating for iron deficiency in an older adult

o Serum iron is not an adequate test to exclude iron deficiency, nor does a normocytic anemia exclude iron deficiency. Microcytosis is a late finding of severe iron deficiency. Failure to recognize iron deficiency could result in a delay in diagnosis of a gastrointestinal or urinary malignancy.

Failure to pursue further evaluation after transfusing RBCs and temporarily improving the Hb

Not recognizing the importance of abnormalities in the CBC count other than measures of the RBCs

o High or low platelet levels, WBCs, or abnormal cells in the blood (eg, blasts) should prompt a hematology referral.

Failure to recognize that anemia is a sign of life-threatening but potentially curable disease (eg, lymphoma, hairy cell leukemia)

Inappropriately treating anemia with ESAso These drugs have been studied for discrete diseases, have considerable risks, and

require close patient monitoring.