Primary Care Reports October 6, 1997

Diagnosis and Management of Anemia

Author: David R. Little, MD, MS, Wright State University, Department of Family Medicine, Dayton, OH.

Peer Reviewer: Gary L. Nicholson, MD, Medical Oncologist/Hematologist, Dayton Oncology/Hematology Consultants, Dayton, OH.

Editor’s Note—Anemia is a clinical syndrome that presents many diagnostic and therapeutic challenges to the primary care physician. This article presents a series of algorithms that will enable the clinician to develop a focused approach to the diagnosis and avoid excessive laboratory testing.

Microcytic anemia commonly results from iron deficiency, chronic disease, lead toxicity, or disorders of hemoglobin synthesis. These conditions can usually be distinguished on the basis of serum iron, ferritin, and lead levels, along with an occasional hemoglobin electrophoresis.

The differential diagnosis for normocytic anemia includes acute blood loss, chronic disease, bone marrow failure, hypersplenism, and hemolytic anemia. The reticulocyte index provides key information about adequacy of bone marrow response to anemia, while the peripheral smear and the indirect Coombs’ test are helpful in identifying hemolysis. Evidence of bone marrow failure will necessitate a marrow aspiration and biopsy.

Most cases of macrocytic anemia result from deficiency of vitamin B12, folic acid, or both. Serum assays for these nutrients, along with the peripheral smear and the reticulocyte count, will clarify the diagnosis in most cases. The role of drugs and toxins in producing anemia is also essential to consider. Drugs may be responsible for a variety of types of anemia through various mechanisms, which are reviewed in this issue.

Once the precise etiologic diagnosis of anemia is confirmed, underlying causes must be determined. Anemia is often a sign of significant underlying illness. This article reviews the common causes of anemia, practical treatment approaches, and clinical implications associated with each condition.

Introduction

Anemia is a common clinical syndrome that primary care physicians are often called upon to diagnose and manage. The prevalence of anemia in the U.S. has been reported at 29-30 cases per 1000 in the female population across all age groups. In males, the prevalence is 6.0 cases per 1000 under age 45 and rises to a peak of 18.5 cases per 1000 men over age 75.1 A targeted approach to the laboratory evaluation of the anemic patient will assist the clinician in achieving an efficient, cost-effective diagnosis. Accurate diagnosis for the underlying cause of anemia is critical, because it may be an indicator of significant underlying illness.

Anemia is defined as a reduction of the total red blood cell volume (hematocrit) or the concentration of blood hemoglobin.2 The normal values for hematocrit and hemoglobin vary with age and gender. (See Table 1.) Results must also be interpreted in the context of coexisting medical conditions. For example, patients with severe pulmonary disease would be expected to have an elevated hematocrit. Normal values in this context may actually represent a reduction of the total RBC volume.

Clinical Features

The clinical presentation of anemia is widely variable. In some cases, it may present with non-specific signs and symptoms such as fatigue, shortness of breath, pallor, and tachycardia. The presence of conjunctival pallor was recently demonstrated to correlate well with severe anemia.3 Many cases of anemia are discovered incidentally, or as a manifestation of another known disease process.

The medical history should focus on clues to the etiology of the anemia. Important questions include chronic blood loss from stool, urine, epistaxis, menstruation, or other foci. A history of exposure to drugs and toxins, including alcohol, is essential. A thorough family history will point to hereditary causes, and a complete review of systems may reveal other evidence of hepatic, renal, thyroid, or rheumatologic disease.

Physical examination should be directed toward clues to underlying illnesses. Specific evidence of rheumatologic disease, liver disease, endocrine disease, and malignancy should be sought. The presence of lymphadenopathy or splenomegaly is an important finding that may correlate with infection, leukemia, or lymphoma. Digital rectal exam is essential to detect mass lesions of the colon or prostate and to test for occult fecal blood loss. Suspected fecal blood loss may require multiple stool guaiac tests to detect.4

Laboratory Testing. The complete blood count (CBC) is the most commonly used laboratory test in evaluating anemia. The CBC will contain quantitative information about the contents of the blood (hemoglobin, hematocrit, and red blood cell count) and measures of the size and hemoglobin concentration of the red blood cells.5 The measurements of red cell size and hemoglobin content are very useful in classifying cases of anemia and determining their potential causes. The white blood cell and platelet counts included in the CBC may also have implcations in the evaluation of certain causes of anemia.

The CBC will also contain the red cell distribution width (RDW), an index of the variability of red cell size. Larger values of the RDW indicate a more heterogenous red cell population. The RDW is an early indicator of some forms of anemia, particularly early iron deficiency.6 In combination with the mean cell volume, the RDW can be used to classify causes of anemia.7

The peripheral blood smear may reveal characteristic abnormalities of RBC morphology that can be diagnostic of certain conditions, such as sickle cell disease, spherocytosis, and mechanical hemolytic anemias. Examples of other important diagnostic information available on the peripheral smear will be discussed throughout this article.

A wide variety of additional laboratory studies are available to assist the clinician in confirming the etiology of anemia. Selective use of these tests, as described by the algorithms presented here, will aid in the diagnosis without resorting to a more costly, "shotgun" approach to laboratory testing.

Classification of Anemias. It is useful to classify anemias on the basis of the mean corpuscular volume (MCV). The normal range for MCV in adults is approximately 80-100 femtoliters (fL). Values of MCV within this range are termed normocytic. Values below 80 fL and above 100 fL are termed microcytic and macrocytic, respectively. RBCs are also classified according to hemoglobin content. Normochromic cells have a mean corpuscular hemoglobin concentration (MCHC) of 32-36 g/dL. Cells with an MCHC below 32 are termed hypochromic. Values above the normal range are seen only rarely, predominantly in spherocytic disorders.2

Microcytic Anemias (See Figure 1)

Iron-deficiency anemia. A low ferritin level (< 30 ng/mL) confirms the diagnosis of iron deficiency.8 Iron deficiency is the most common cause of anemia throughout the world.2 When iron deficiency is discovered, the underlying cause must be sought. In children, this deficiency is typically dietary.9 In adults, iron deficiency should be considered to represent chronic blood loss until proven otherwise. A list of potential causes of iron-deficiency anemia is presented in Table 2.

Management. Once the underlying cause has been addressed, many cases of iron deficiency can be treated successfully with oral iron supplementation. A variety of oral iron preparations are available at relatively low cost. Sulfate, fumarate, and gluconate salts are most commonly used; none offers a distinct advantage in bioavailability.10 Enteric-coated preparations are ineffective since the stomach is the optimum site of absorption. Optimum delivery of oral iron requires the capsule to dissolve rapidly in the stomach, so that the iron may be absorbed in the duodenum and upper jejunum. Enteric-coated tablets dissolve poorly and are ineffective for iron replacement.

Oral iron supplementation is best administered as a daily dose of ferrous sulfate, the least expensive preparation. A course of 150-200 mg elemental iron daily should be given for 4-6 months or until the target hemoglobin level has been achieved. Replacement therapy is usually continued for another 4-6 months or until the serum ferritin level reaches 50 ng/mL, reflecting adequate body iron stores.11 Absorption of oral iron may be limited by antacids, H2 blockers, or proton pump inhibitors due to the reduced stomach acid content associated with these agents. Caffeine intake, particularly in the form of tea, will also reduce absorption.10,12

Failure of the patient to respond to oral iron supplementation may indicate an inability to absorb iron. This may be confirmed by measuring the serum iron level at two and four hours after an oral dose of 325 mg ferrous sulfate. Failure of the iron level to increase by 115 mcg/dL over pretreatment values indicates iron malabsorption.10

In the event of an inadequate response to oral iron supplementation, parenteral treatment with iron dextran should be considered. Specific indications for parenteral iron include: 1) inability to tolerate oral iron; 2) non-compliance with medication; 3) iron malabsorption after acid reduction surgery; or 4) continued blood loss.13 Due to the unpredictable absorption and local complications of intramuscular administration, the intravenous route is preferred for parenteral iron treatment.

Parenteral iron dextran may be administered as a single dose. The total dose required to replenish body stores is based upon body weight and hemoglobin deficit. The dosage may be determined from standard nomograms accompanying the product.

The primary concern with intravenous iron dextran is the occurrence of adverse reactions. Immediate reactions may include headache; dyspnea; flushing; chest, abdominal, or back pain; nausea and vomiting; fever; hypotension; seizures; urticaria; and anaphylaxis. A small test dose should be given to observe the patient for an anaphylactic reaction.14 If the test dose is tolerated, the full dose infusion may be given at a rate of 50 mg/min, up to a total daily dose of 100 mg.

Anemia of Chronic Disease. Anemia of chronic disease (ACD) is defined as "the anemia that accompanies chronic inflammatory, infectious, or neoplastic disorders."15 Examples of conditions that may be associated with ACD are listed in Table 3. ACD is a common condition, second in incidence only to iron-deficiency anemia. It occurs as the result of decreased production of red cells in the context of an underlying illness. Although ACD is traditionally categorized as normochromic and normocytic, it can be microcytic in 30-50% of cases.

Some authors have subdivided ACD into separate categories according to differing pathophysiology. The anemia of chronic renal failure results from an absolute deficiency of erythropoietin. Anemias caused by endocrine dysfunction are often multifactorial, featuring a relative deficiency of erythropoietin. Anemia caused by malignancy, infections, and other inflammatory processes is the result of a "pseudo" iron deficiency. In these situations, iron is trapped within macrophages and becomes unavailable for erythropoiesis.

When ACD is microcytic, it is characterized by a relatively mild decrease in MCV, usually not less than 70 fL. This is accompanied by a normal or mildly elevated ferritin, low serum iron, low total iron-binding capacity, and low transferrin saturation. Differentiating ACD from iron-deficiency anemia may require additional testing. An elevated sedimentation rate is seen in ACD.16 The serum transferrin receptor level is normal in ACD but markedly elevated in iron deficiency.16,17 In some patients, iron-deficiency anemia may coexist with ACD. In this situation, a favorable response to iron supplementation will occur in the context of another chronic illness. Patients receiving dialysis may experience a microcytic anemia as the result of aluminum intoxication.

Management. The first objective in the management of ACD is to identify and treat the underlying cause. In many instances, no specific therapy will be necessary for the anemia. Transfusion therapy is the traditional standard for severe cases, but it is associated with significant costs and potential risks. A newer alternative to transfusion for patients with ACD is recombinant human erythropoietin (rhEPO).

Erythropoietin has been proven to be effective in correcting the anemia associated with many chronic conditions, including chronic renal failure,18 rheumatoid arthritis,19 cancer (with or without chemotherapy),20 and AIDS.21 The results of therapy include an improved hematocrit, less need for transfusions, and improvement in overall functional status.15

The preferred route of administration for rhEPO is subcutaneous. A dose of 25-250 U/kg is given three times weekly for 8-12 weeks. Treatment will result in an improvement of hemoglobin of 2 g/dL or more in greater than 50% of patients.15 Side effects are rare, but accelerated hypertension may occur in patients with renal failure. These individuals must be monitored closely during rhEPO therapy. There are no other contraindications to the use of rhEPO. The main factor limiting rhEPO treatment is cost. In our institution, the pharmacy cost for a single vial of rhEPO (10,000 Units, generally a single dose) is $193.

Lead Toxicity. Lead toxicity may present with a microcytic anemia. The characteristic feature of this anemia is the presence of basophilic stippling of RBCs on the peripheral blood smear. Blood lead testing will confirm the diagnosis. Generally, other symptoms of lead intoxication (neuro- and ototoxicity) will precede the appearance of the anemia.22 Screening of other family members and a thorough investigation of the patient’s environment should follow.

Hemoglobin Disorders. The presence of a microcytic anemia that is not attributable to iron deficiency, chronic disease, or lead toxicity suggests an underlying disorder of hemoglobin synthesis. These disorders may be categorized as hemoglobinopathies (production of abnormal hemoglobin) or thalassemia (underproduction of normal hemoglobin due to an absence or deficiency of normal variant chains).23

Most hemoglobin disorders present with a mild-to-moderate microcytic anemia with striking morphologic abnormalities. Electrophoresis will confirm the diagnosis, depending upon the precise hemoglobin variant discovered. (See Table 4.) These disorders may be difficult to distinguish from iron deficiency or may be exacerbated if iron deficiency is also present. Iron deficiency typically has an elevated RDW, while in hemoglobin disorders it remains normal. Other indices of RBC heterogeneity may also assist in the diagnosis.24

Severity of clinical illness is based upon the underlying genetic expression of the disorder. Homozygosity for hemoglobin disorders such as sickle cell disease and beta-thalassemia will result in severe illness. It is estimated that only 750-1000 patients with homozygous beta-thalassemia are present in North America, predominantly among individuals of Mediterranean, Asian, or African descent.25 Heterozygous expression of hemoglobin disorders (such as sickle cell trait and thalassemia trait) will present with a mild anemia which usually requires no further intervention. Alpha-thalassemia minor occurs primarily in Asian patients and may present periodically in areas with large Asian-American populations. Discovery of such a molecular defect should lead to screening of other family members and genetic counseling to explore the implications of potentially homozygous offspring.

Microcytic anemia may also be seen in some cases of RBC membrane defects such as hereditary spherocytosis (HS). HS may often be diagnosed directly from the peripheral smear.

Normocytic Anemia (See Figure 2)

The normocytic anemias may be divided into two broad etiologic categories: increased destruction (or loss) of red blood cells and decreased RBC production. The distinguishing feature between these categories is the reticulocyte count, which measures the compensatory response to the anemia. Because the reticulocyte count is expressed as a percentage of total RBCs, it will increase in proportion to the severity of the anemia. For this reason, the count is usually corrected to a normal hematocrit of 45% using the following formula:2

Corrected Reticulocyte Count = Retic. Count ´ Hematocrit/45

Normocytic anemias of decreased RBC production

Bone Marrow Failure. Bone marrow failure should be suspected in cases of normochromic, normocytic anemia accompanied by a markedly decreased reticulocyte count (< 0.5%), leukopenia and/or thrombocytopenia, or characteristic abnormalities of the peripheral blood smear including teardrop cells, nucleated RBCs, and immature granulocytes.2 Involvement of multiple cell lines (red cells, white cells, and/or platelets), or the presence of abnormal cells point toward bone marrow failure. Precise pathologic diagnosis in these patients will require bone marrow aspiration and biopsy. Conditions that may cause bone marrow failure include aplastic anemia, myelodysplastic syndromes, and acute myelogenous leukemia,5 metastatic disease of the bone marrow, myelofibrosis, pure red cell aplasia, and aplastic crises accompanying hemolytic anemias.

Aplastic Anemia. Aplastic anemia is the condition that most commonly causes bone marrow failure. It is defined as a failure of blood cell production resulting in pancytopenia with a markedly hypocellular bone marrow.5 The documented incidence of aplastic anemia in the United States and other developed countries is 5-10 cases per one million population per year. Most cases of aplastic anemia (65%) are idiopathic and appear to be related to immune-system-mediated destruction of bone marrow cells.26 Heredity plays a role in some cases, with an association between aplastic anemia and the presence of the HLA-DR2 antigen,27 and the appearance of aplastic anemia with the autosomal recessive Fanconi syndrome in childhood. Viral infections, including hepatitis,28 radiation, and exposure to drugs and chemicals have also been implicated in causing aplastic anemia.

Mild cases of aplastic anemia may remit or may be managed conservatively. Severe aplastic anemia may be defined by a reticulocyte count < 1%, an absolute neutrophil count < 500 mm3, and a platelet count < 20,000/mm3. These cases may require more aggressive management. Treatments for aplastic anemia include bone marrow transplantation or immunosuppressive therapy.29 Marrow transplants are preferred in patients before age 20 and in whom little or no transfusion therapy has been provided. Survival after successful transplant approaches 70% at 15 years.30 Immunosuppressive therapy is the treatment of choice for patients over 40 years of age.29 The survival rate in this population drops to 38% at 15 years, and relapse occurs more commonly.30

Other hypoproliferative anemias. Anemia of chronic disease, in its normocytic form, will present with a suboptimal reticulocyte response but no evidence of bone marrow failure. Drugs and toxins may also cause reduced RBC production. (See Table 5.) "Mixed" disorders (coexisting microcytic and macrocytic conditions) may present a picture of normocytic anemia with a markedly elevated RDW. Normocytic anemia may be idiopathic in 3-30% of cases, particularly in elderly patients.31 This so-called "anemia of senescence" is a controversial entity. These patients should be investigated for chronic blood loss and other underlying illnesses; however, bone marrow examinations in this situation have very low diagnostic yield.

Normocytic anemia due to RBC destruction/loss

Acute Blood Loss. Normocytic anemia with increased RBC destruction may be due to acute blood loss. In most cases, the presentation will be fairly evident unless the source of blood loss is occult, such as a hip fracture or a retroperitoneal bleed. Reticulocyte counts require 3-5 days to mount a significant response to acute blood loss. It is useful diagnostically to observe the rate of fall of hemoglobin levels. A rapid drop is seen with acute blood loss, hemolysis, or hemodilution. Bone marrow failure, by contrast, will produce a much more gradual reduction.

Hypersplenism. Increased phagocytic activity within the spleen may lead to sequestration and destruction of red blood cells.32 The result is the characteristic triad of anemia (and/or leukopenia), splenomegaly, and bone marrow hyperplasia. Hypersplenism may be the result of portal hypertension, myeloproliferative disorders, or chronic infections. Splenomegaly may also be present in hemolytic diseases and hemoglobinopathies as fragile RBCs are captured and destroyed. Splenectomy may be beneficial to correct anemia and reverse portal hypertension, but infectious and thrombotic complications may result.5 Pneumococcal vaccine should be administered prior to splenectomy.

Hemolytic anemia (See Figure 3). Hemolytic anemia should be suspected in cases of normocytic anemia without acute bleeding, marrow insufficiency, or hypersplenism. The presence of hemolysis will be further supported by increased indirect bilirubin and lactate dehydrogenase. Serum haptoglobin will be decreased in cases of intravascular hemolysis. There are many conditions that may cause hemolytic anemia, as listed in Table 6.

Hemolytic disease may be divided into two broad categories: 1) conditions caused by intrinsic red cell anomalies and 2) those resulting from extrinsic factors.

Intrinsic red cell anomalies include cell membrane defects (such as spherocytosis), red cell enzyme defects (such as G6PD and pyruvate kinase), and hemoglobinopathies. Many of these conditions may be identified by characteristic findings on the peripheral smear. A normal peripheral smear in the setting of a hemolytic anemia is most likely to be found in either an autoimmune hemolytic anemia or a red cell enzyme defect. Therefore, hemolysis in the presence of a normal peripheral smear and a negative Coombs test suggests an enzyme defect such as G6PD deficiency or pyruvate kinase deficiency.

Extrinsic conditions producing hemolytic anemia include mechanical factors, such as prosthetic heart valves, DIC, burns, neoplasms, or malignant hypertension.2 The peripheral smear in these cases may reveal schistocytes (RBC fragments). Autoimmune antibodies are another extrinsic cause of hemolysis, as seen in transfusion reactions, Rh incompatibility, drug-induced hemolytic anemia, and warm or cold-reacting autoantibodies. Microangiopathic processes, infections, and chemical agents are other extrinsic factors that may be associated with hemolytic anemia. (See Table 6.)

Management. Management of hemolytic anemia should be directed at the underlying cause. Most patients with prosthetic heart valves will respond to administration of iron and folate supplementation. More severe cases may require replacement of the prosthesis. Recombinant erythropoietin has been successful in a few cases of mechanical hemolysis.33 Offending drugs should be discontinued, and exposure to environmental agents strictly limited. Autoimmune hemolysis may respond to corticosteroids or other immunosuppressive agents.5 Transfusion therapy and splenectomy may provide benefit in severe cases.

Macrocytic Anemia (See Figure 4)

Macrocytic anemia is defined by a mean corpuscular volume greater than 100 femtoliters. The first issue to address in diagnosing macrocytic anemia is to determine whether it is megaloblastic or non-megaloblastic. The best way to make this distinction is to examine the peripheral smear. Macrocytic features that may be identified on the smear include hypersegmented neutrophils and oval macrocytes. Extremely high MCV values (> 120 fL) are usually associated with megaloblastic anemia.34 An elevated LDH is suggestive of pernicious anemia as the result of hemolysis occurring within the bone marrow. On some occasions, megaloblasts may not appear in the peripheral smear. If the precise diagnosis of a macrocytic anemia cannot be achieved with B12 and folate assays, bone marrow examination may be necessary. The appearance of megaloblasts in the marrow may be so bizarre that the diagnosis may be mistaken for acute leukemia.

Megaloblastic Anemia. Megaloblastic anemia is most often the result of a deficiency of vitamin B12 and/or folic acid. These illnesses present a characteristic clinical picture which includes glossitis, gastrointestinal symptoms, and mild leukopenia and thrombocytopenia. The distinctive clinical feature of B12 deficiency is the presence of neurologic symptoms. Diagnosis of B12 or folate deficiency can be confirmed by the laboratory finding of decreased blood levels of these nutrients.

If a megaloblastic anemia does not appear to result from B12 or folate deficiency, it is important to take a careful history of medication use. Folate antagonists, antimetabolites, and other drugs may cause megaloblastic anemia. (See Table 5.) If nutrient deficiency cannot be confirmed and no drug use is apparent, referral to a hematologist is recommended for further evaluation.

Vitamin B12 Deficiency. Deficiency of vitamin B12 is generally the result of a prolonged failure of absorption, since body B12 stores are adequate for up to five years. Pernicious anemia, Crohn’s disease, and drug therapy (see Table 5) are the most frequent causes.35 Post-surgical states, including post-total gastrectomy, surgical creation of a "blind loop," or ileal resection frequently result in an inability to absorb B12. Strict vegetarianism may result in B12 deficiency, but, in general, nutritional intake is more than adequate to sustain bodily needs. Laboratory diagnosis of B12 deficiency may be confirmed by the findings of increased urinary methylmalonic acid36 and serum homocysteine.37

Pernicious Anemia. Pernicious anemia is by far the most common cause of B12 deficiency. This condition is especially common among the elderly, with an observed prevalence of up to 1.9%.38 Pernicious anemia is caused by intestinal malabsorption due to atrophy of the gastric mucosa and decreased secretion of intrinsic factor. One recent hypothesis suggests an autoimmune mechanism, as illustrated by a case of spontaneous remission of pernicious anemia after corticosteroid therapy.39 The question of a relationship between pernicious anemia and Helicobacter pylori has also been investigated, but evidence for this theory has not been conclusive.40,41

The diagnosis of pernicious anemia may be confirmed by the use of Schilling’s test.35 Failure to absorb radiolabelled B12 on the initial assay, followed by absorption when B12 is coadministered with intrinsic factor, establishes the diagnosis. Treatment of pernicious anemia consists of intramuscular injections of 1000 mcg of vitamin B12 at weekly intervals until B12 stores are replenished, followed by monthly injections for life.42 Oral and intranasal preparations of B12 have been tried but without compelling success.43

Management of pernicious anemia should include surveillance for the development of gastric carcinoma. Preliminary reports suggest that routine endoscopic studies may be necessary for screening and early detection of this associated malignancy.44,45

Folate Deficiency. Folic acid deficiency is characterized by a megaloblastic anemia with a reduction in serum folate levels. Most cases of folate deficiency are a result of inadequate intake, increased folate requirements, or both.35 Poor folate intake may occur with alcoholism, poverty, or advanced age. Body folate stores are marginally adequate, so reduced folate intake will result in a deficiency state in only 2-4 months. Increased folate demands are present during pregnancy and adolescence, especially during growth spurts. Drug therapy, including phenytoin, phenobarbital, sulfasalazine, and methotrexate, may also lead to folate deficiency.

Diagnosis of folate deficiency may require additional laboratory testing, due to the limitations of the serum folate assay.46 Serum folate levels may transiently return to the normal range even after one folate-rich meal. Red blood cell folate levels are a more consistent measure of folate balance over a period of months. The homocysteine level will be increased, as in B12 deficiency; however, methylmalonic acid levels are normal in folate deficiency and elevated in B12 deficiency. The distinction between B12 and folate-deficient states is important, since B12 deficiency is associated with progressive neurologic deficits. Treating these patients with folic acid may produce transient hematologic improvements, masking the clinical symptoms of B12 deficiency while neurologic deterioration continues. This possibility has given rise to a debate over the value of food fortification with folic acid.47

Treatment of folate deficiency is straightforward. In the absence of a folate malabsorption state (such as tropical sprue), a daily dose of 1 mg folic acid given orally will replenish body stores in about three weeks.35 Routine folic acid supplementation is recommended for women of child-bearing age to minimize the risk of fetal neural tube defects.

Non-megaloblastic Macrocytic Anemia. The most common cause of non-megaloblastic macrocytic anemia is alcoholism. The anemia may result from folate deficiency or from the direct toxic effects of alcohol upon the bone marrow. Macrocytosis may also appear as a result of reticulocytosis, since reticulocytes are larger than mature RBCs and their presence will cause a higher mean corpuscular volume. Hemolytic anemia, acute blood loss, or hypersplenism may cause this picture.

Non-megaloblastic macrocytic anemia with a low reticulocyte count may be seen with chronic diseases, most commonly liver disease and hypothyroidism. Aplastic anemia may also produce this picture, so bone marrow examination is advisable.

Myelodysplastic syndromes may produce an anemia characterized by the presence of macro-ovalocytes on the peripheral smear. Bone marrow examination will reveal dysplasia, sometimes with the presence of "megaloblastoid" cells.

Summary

Use of the algorithms presented here will assist the clinician in establishing the precise diagnosis for anemia in a cost-effective fashion, while avoiding the more expensive "shotgun" approach. Accurate diagnosis of anemia is essential, since it represents a clinical syndrome that is frequently associated with significant underlying illness.

References

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2. Brown RG. Anemia. In: Taylor RB (ed). Family Medicine: Principles and Practice, 4th ed. New York: Springer-Verlag; 1994:997-1005.

3. Sheth TN, et al. The relation of conjunctival pallor to the presence of anemia. J Gen Int Med 1997;12:102-106.

4. Mandel JS, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993;328: 1365-1371.

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7. Bessman JD, et al. Improved classification of anemias by MCV and RDW. Am J Clin Path 1988;80:322-326.

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9. Centers for Disease Control and Prevention. Guidelines for school health programs to promote lifelong healthy eating. MMWR Morb Mortal Wkly Rep 1996;45:1-41.

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11. Cook JD. Iron deficiency anemia. In: Brain MC, Carbone P (eds). Current Therapy in Hematology and Oncology, 3rd ed. St. Louis: Mosby-Year Book; 1987:9-11.

12. Gabrielli GB, De Sandre G. Excessive tea consumption can inhibit the efficacy of oral iron treatment in iron-deficiency anemia. Haematologica 1995;80:518-520.

13. Glass J. Iron deficiency anemia. In: Rakel RE (ed). Conn’s Current Therapy; 1997:349-352.

14. Burns DL, et al. Parenteral iron dextran therapy: A review. Nutrition 1995;11:163-168.

15. Krantz SB. Pathogenesis and treatment of the anemia of chronic disease. Am J Med Sci 1994;307:353-359.

16. Ahluwalia N, et al. Iron deficiency and anemia of chronic disease in elderly women: A discriminant-analysis approach for differentiation. Am J Clin Nutr 1995;61:590-596.

17. Ferguson BJ, et al. Serum transferrin receptor distinguishes the anemia of chronic disease from iron deficiency anemia. J Lab Clin Med 1992;19:385-390.

18. Eschback JW, et al. Treatment of the anemia of progressive renal failure with recombinant human erythropoeitin. N Engl J Med 1989;321:158-163.

19. Peeters HR, et al. Effect of recombinant human erythropoeitin on anaemia and disease activity in patients with rheumatoid arthritis and anaemia of chronic disease: A randomised placebo controlled double blind 52 weeks clinical trial. Ann Rheum Dis 1996;55:739-744.

20. Ludwig H, et al. Recombinant human erythropoeitin for the correction of cancer-associated anemia with and without concomitant cytotoxic chemotherapy. Cancer 1995;76:2319-2329.

21. Henry DA, et al. Recombinant human erythropoeitin in the treatment of anemia associated with human immunodeficiency virus (HIV) infection and zidovudine therapy: Overview of four clinical trials. Ann Intern Med 1992;117:739-748.

22. Chao J, Kikano GE. Lead poisoning in children. Am Fam Phys 1993;47:113-128.

23. Nguyen AN, et al. A rule-based expert system for laboratory diagnosis of hemoglobin disorders. Arch Pathol Lab Med 1996;120:817-27.

24. Liu T, et al. The erythrocyte cell hemoglobin distribution width segregates thalassemia traits from other nonthalassemic conditions with microcytosis. Am J Clin Path 1997;107:601-607.

25. Pearson HA, et al. The changing profile of homozygous beta-thalassemia: Demography, ethnicity, and age distribution of current North American patients and changes in two decades. Pediatrics 1996;97:352-356.

26. Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood 1995;85:3367-3377.

27. Nimer SD, et al. An increased HLA DR2 frequency is seen in aplastic anemia patients. Blood 1994;84:923-927.

28. Brown KE, et al. Hepatitis-associated aplastic anemia. N Engl J Med 1997;336:1059- 1064.

29. Fonseca R, Tefferi A. Practical aspects in the diagnosis and management of aplastic anemia. Am J Med Sci 1997;313:159-169.

30. Doney K, et al. Primary treatment of acquired aplastic anemia: Outcomes with bone marrow transplantation and immunosuppressive therapy. Ann Intern Med 1997;126:107-115.

31. Elis A, et al. A clinical approach to "idiopathic" normocytic-normochromic anemia. J Am Geriatr Soc 1996;44:832-834.

32. Shah SHA, et al. Measurement of spleen size and its relation to hypersplenism and portal hemodynamics in portal hypertension due to hepatic cirrhosis. Am J Gastroenterol 1996;91:2580-2583.

33. Kornowski R, et al. Erythropoeitin therapy obviates the need for recurrent transfusions in a patient with severe hemolysis due to prosthetic valves. Chest 1992;102:315.

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39. Span J, et al. A reversible case of pernicious anemia. Am J Gastroenterol 1993;88:1277-1278.

40. Haruma K, et al. Pernicious anemia and Helicobacter pylori infection in Japan: Evaluation in a country with a high prevalrnce of infection. Am J Gastroenterol 1995;90:1107-1110.

41. Varis O, et al. Is Helicobacter pylori involved in the pathogenesis of the gastritis characteristic of pernicious anaemia? Scand J Gastroenterol 1993;28:705-708.

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43. Pruthi RK, Tefferi A. Pernicious anemia revisited. Mayo Clin Proc 1994;69:144-150.

44. El-Newihi HM, et al. Gastric cancer and perniciouc anemia appearing as pseudoachalasia. Southern Med J 1996;89:906-910.

45. Sjoblom SM, et al. Gastroscopic follow-up of pernicious anemia patients. Gut 1993;34:28-32.

46. Swain RA, St. Clair L. The role of folic acid in deficiency states and prevention of disease. J Fam Pract 1997;44:138-144.

47. Dickinson CJ. Does folic acid harm people with vitamin B12 deficiency? Q J Med 1995;88:357-364.

Physician CME Questions

++++

A microcytic anemia with a low serum ferritin level is most likely the result of:

a. chronic disease.

b. thalassemia minor.

c. lead toxicity.

d. iron deficiency.

e. hypersplenism.

::::

Iron deficiency anemia in adults:

a. should be confirmed by hemoglobin electrophoresis.

b. is seen only infrequently compared to other anemias.

c. should be considered to represent chronic blood loss until proven otherwise.

d. should be confirmed by bone marrow examination.

e. can routinely be considered an incidental finding.

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The presence of schistocytes on a peripheral blood smear usually signifies:

a. Sickle cell disease

b. Bone marrow failure

c. Iron deficiency

d. Hypersplenism

e. Mechanical hemolysis

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The diagnosis of megaloblastic anemia:

a. Can often be made on the basis of the peripheral blood smear

b. Requires hemoglobin electrophoresis

c. Requires bone marrow examination

d. May result from hemolytic disease or hypersplenism

e. All of the above

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