Anemia, Sideroblastic

Anemia is a condition rather than a disease. Thus, it does not qualify as a diagnosis and the underlying cause must always be identified. Anemia has over 100 different underlying causes. Busy physicians may be tempted to prescribe iron or vitamins without a thorough investigation. Furthermore, frequent noncompliance with empiric trials of iron supplementation makes judging patient response difficult in many cases. Even if supplementation is effective in the treatment of iron deficiency, colon cancer or other pathology may be the underlying cause. Therefore, an organized approach to the investigation of anemia is important.

Definition and Clinical Presentation

Anemia is usually defined as a decreased concentration of hemoglobin in the blood. The concentration of hemoglobin is easy to measure, and although a decrease in the red blood cell (RBC) mass may be a more exact definition of anemia, it is difficult to measure.[1] The patient's volume status must always be taken into consideration when hemoglobin is described as a concentration (g per dL), lest a significant anemia be masked by dehydration (hemoconcentration) or a mild anemia be exaggerated by overhydration (hemodilution). Table 1 shows the cut-off values for normal hemoglobin at sea level.[2]

(*)--Range of normal may differ slightly in different laboratories. Also, a person with a "high-normal" hemoglobin that falls to a "low-normal" hemoglobin may be iron deficient, even though the hemoglobin is still in the normal range.

The presentation of anemia varies from an emergency, in cases of acute blood loss, to asymptomatic, in cases of mild iron deficiency. This variability in the spectrum of presentation is dependent on the abruptness of onset, the severity of anemia and the ability of the cardiopulmonary system to compensate. When the onset is gradual, few symptoms are noted until the hemoglobin concentration is 8 g per dL (80 g per L) or lower.[3] Initially, dyspnea and mild fatigue occur with strenuous exercise (i.e., exercise intolerance). Later, resting tachycardia and a high output systolic murmur may be noted. High output cardiac failure occurs in the most severe cases or in patients with underlying cardiac disease. Pallor is most evident in the mucous membranes of the mouth, lips, conjunctivae, nail beds and palmer skin crease. Elements of a thorough history are listed in Table 2.

NSAID = nonsteroidal anti-inflammatory drugs.

Reprinted with permission from Shine JW. Women's medicine. In: Blackwell R, ed. Anemia. Cambridge, Mass.: Blackwell Science, Inc., 1996:205-12.

Classification

The many causes of anemia can be classified by three basic mechanisms: (1) blood loss, (2) destruction of RBCs (hemolysis) and (3) decreased production of RBCs. The reticulocyte count is often used to distinguish increased RBC destruction from decreased RBC production.[4] A classification system based on RBC morphology from the peripheral blood smear and RBC size and hemoglobin content (as determined from RBC indexes) is also widely used to classify anemias.

The automated complete blood cell count (CBC) provides an electronically measured mean corpuscular volume (MCV), an RBC count and hemoglobin concentration. In addition, many electronic counters calculate RBC distribution width (RDW), which is a measure of the size variation in all of the RBCs counted. Based on the MCV (normal range in adults: 78 to 98 [micro][m.sup.3] [78 to 98 fL]), anemia can be classified as microcytic (less than 78 [micro][m.sup.3] [78 fL]), normocytic (78 to 98 [micro][m.sup.3] [78 to 98 fL]) or macrocytic (greater than 98 [micro][m.sup.3] [98 fL]). This measurement is accurate as long as all of the RBCs are similar in size.

The RDW (normal range: 11.5 to 14.5 percent) is a calculated index that quantifies the amount of variation in the size of RBCs. If the RBC size varies (anisocytosis), the RDW will be elevated, thus indicating that the MCV is less reliable. Initially, an elevated RDW was believed to differentiate iron deficiency from other causes of microcytic anemia. While iron deficiency is the most common cause of RDW elevation, it has been shown that thalassemia, hemoglobinopathies and other causes of microcytic anemia can also elevate the RDW.[5]

Examination of the peripheral blood smear can be invaluable in the classification of anemia. The normal RBC is similar in size to the nucleus of a small lymphocyte. The hemoglobin content is estimated by observing the central pallor of the RBC. Normally, the central pallor has a diameter about one third that of the entire cell. When the central pallor takes up more area, the RBC is considered hypochromic.

One of the most important tests in the differential diagnosis of microcytic anemia is the serum ferritin level, which gives an estimate of the body's iron stores. Apart from bone marrow aspiration, the serum ferritin level is considered the most powerful single test for the diagnosis of iron deficiency anemia.[6-8]

A low serum ferritin level is diagnostic of iron deficiency and is seen very early in the disease process. Ferritin is, however, an acute phase reactant. In the presence of liver disease, chronic inflammatory diseases (e.g., rheumatoid arthritis) or malignancy, the ferritin level may be falsely elevated. Nevertheless, the serum ferritin level retains its usefulness in the diagnosis of iron deficiency anemia in these patients. Traditionally, a cut-off value of 10 to 15 ng per mL (10 to 15 [micro]g per L) is considered confirmatory of iron deficiency in patients without chronic inflammatory conditions, with a range of higher values (50 to 100 ng per mL [50 to 100 [micro]g per L]) given as a cutoff in patients with chronic inflammation.

A recent meta-analysis[5] of over 50 studies suggests that iron deficiency is unlikely at serum ferritin levels greater than 40 ng per mL (40 [micro]g per L) for general populations and greater than 70 ng per mL (70 [micro]g per L) in patients with chronic inflammatory conditions. A ferritin level of less than 15 ng per mL (15 [micro]g per L) is confirmatory of iron deficiency in all populations. Intermediate values require further investigation by other laboratory parameters.[6] Although seldom required, the gold standard for identifying patients with iron deficiency is a bone marrow aspiration, which will show absent iron stores early in the course of iron deficiency.

Differential Diagnosis of Microcytic Anemia

Causes of microcytosis are listed in Table 3. The algorithm in Figure 1 shows the work-up and differential diagnosis for this type of anemia.

Table 4 shows the spectrum of laboratory values at different stages of iron deficiency anemia.[11] In addition to these changes, the RDW is elevated and the RBC count is decreased. Measurements of transferrin saturation, transferrin receptor level, free erythrocyte, protoporphyrin level and other parameters also are used in some laboratories to measure iron deficiency. These tests add to the cost of evaluation but do not substantially improve on the widely available parameters noted in Figure 1. Once iron deficiency anemia is diagnosed, a cause must be identified.

[Figure 1 ILLUSTRATION OMITTED]

MCV = mean corpuscular volume; MCHC = mean corpuscular hemoglobin concentration; TIBC = total iron binding capacity.

CAUSES OF IRON DEFICIENCY

The most common cause of iron deficiency in adults is chronic blood loss. The likely etiology of blood loss differs according to sex, age and menstrual status. In men, the most likely source of blood loss is the gastrointestinal tract. In menstruating women, the etiology of iron deficiency is usually related to menstrual blood loss. In postmenopausal women, the source of blood loss is more commonly the gastrointestinal tract. Therefore, in nonmenstruating adults, iron deficiency should be assumed to represent gastrointestinal blood loss until proven otherwise. For this reason, it is generally inappropriate to prescribe iron therapy without also seeking the source of blood loss.

In contrast, iron requirements are increased in infants and children and nutritional inadequacy is the most common cause of iron deficiency. Pregnancy is another time when iron requirements are increased (1 g of additional iron is required during each pregnancy[10]). Table 5 lists underlying causes of iron deficiency anemia.

NSAID = nonsteroidal anti-inflammatory drug.

Reprinted with permission from Shine JW. Women's medicine. In: Blackwell R, ed. Anemia. Cambridge, Mass.: Blackwell Science, Inc., 1996:205-12.

TREATMENT

Iron therapy can begin as soon as the diagnosis of iron deficiency is made. It is not necessary to delay iron therapy while the underlying cause is determined. Gastrointestinal side effects of iron supplementation are common but are dose related. A prudent regimen begins with one 325-mg iron tablet daily and increases by one tablet weekly until a three-times-daily dosage is reached. If necessary, the iron may be taken with meals. Although this slows absorption and therefore prolongs therapy, taking the medication with food should limit side effects and improve adherence. The presence of meat or vitamin C in the stomach is known to increase the absorption of iron, while fiber, tea, coffee and antacids decrease absorption.[8]

Combination tablets and controlled-release preparations may offer a slight increase in absorption or fewer side effects, but the added expense of these preparations does not warrant their use in most cases. Standard preparations include ferrous sulfate, 325 mg (65 mg of elemental iron), ferrous gluconate, 325 mg (39 mg of elemental iron), and ferrous fumarate, 325 mg (107 mg of elemental iron).

For iron supplementation in the pediatric population, iron preparations are available in drops, syrup, elixir and tablet forms. Treatment of iron deficiency in children requires 3 to 6 mg of elemental iron per kg, divided into a three-times-daily dosage regimen. Liquid preparations should be given by dropper or by drinking through a straw to avoid dark staining of the teeth.

The initial response to therapy is reticulocytosis noted in the first two weeks. It is reasonable, however, to simply repeat a CBC in one month. With adequate supplement, an increase of at least 1 g per dl (10 g per L) in hemoglobin should be seen, and correction of the anemia usually is complete within six to eight weeks.[7] Nevertheless, replacement therapy should be continued for four to six months to fully replace lost iron stores. Treatment failures usually occur because the therapy is not tolerated (adherence issues) or the diagnosis of iron deficiency is incorrect. Less commonly, treatment fails because excess iron loss is ongoing or absorption of iron is inadequate, as in patients with partial gastrectomy or malabsorption syndromes.

ANEMIA OF CHRONIC DISEASE

Although the anemia of chronic disease is usually normocytic and normochromic, it occasionally is microcytic and hypochromic, necessitating its differentiation from iron deficiency anemia. If the serum ferritin level is normal or increased, the serum iron is low and the TIBC is also decreased, anemia of chronic disease is likely. Occasionally, iron deficiency anemia may coexist with anemia of chronic disease and a trial of iron therapy is reasonable after appropriate investigation.

THALASSEMIA

Thalassemia is a relatively common cause of microcytosis in certain populations. It is a disorder of globin chain synthesis that leads to a compensatory overproduction of the unaffected globin chains. These excess chains tend to aggregate and precipitate in RBCs, causing premature hemolysis. Normal adult hemoglobin consists of four globin chains--two each of two different chain types (Table 6).

Reprinted with permission from Shine JW. Women's medicine. In: Blackwell R, ed. Anemia. Cambridge, Mass.: Blackwell Science, Inc., 1996:205-12.

The homozygous, or major, form of thalassemia is devastating but uncommon since it is usually lethal in utero. The heterozygous form, thalassemia minor, is much more common and often goes undetected. Beta thalassemia is most common in people of Mediterranean origin (Greek, Italian, Northern African), whereas alpha thalassemia is more common in African Americans, affecting 2 percent of that population.[11] About 15 percent of African Americans are carriers for alpha thalassemia trait. Southeast Asians also may be carriers of alpha thalassemia. These same populations also have increased rates of iron deficiency, and correct classification of microcytic anemia can be challenging.

Thalassemia minor is normally asymptomatic and would not be clinically significant if it were not frequently mistaken for iron deficiency anemia. Patients with thalassemia minor are subjected to repeated trials of inappropriate iron therapy and laboratory evaluations for iron deficiency.

Thalassemia minor is usually detected by a routine CBC, which reveals moderate microcytosis (low MCV) with mild anemia. If the RDW and RBC count are normal, the physician should be alerted to the possibility of thalassemia instead of iron deficiency anemia, where the RDW is elevated and the RBC count is decreased. The peripheral smear often shows basophilic stippling of RBCs and an increase in reticulocytes. Serum iron levels are usually normal.

Beta thalassemia is confirmed by-hemoglobin electrophoresis, which reveals an elevated hemoglobin [A.sub.2] (3.75 to 6.5 percent instead of the normal 2 percent). In the presence of iron deficiency, however, this increase is attenuated. Alpha thalassemia is more difficult to confirm. No relative change is apparent in hemoglobin electrophoresis, because each type of hemoglobin has the same two alpha globin chains. However, if the laboratory evaluation is consistent with thalassemia but the hemoglobin electrophoresis is normal or if hemoglobin [A.sub.2] is decreased, alpha thalassemia can be confirmed by noting similar changes in family members. Specific molecular genetic tests are available for alpha thalassemia and can be useful in selected cases.

The diagnosis of thalassemia is important not only to avoid inappropriate iron therapy but also to provide genetic counseling. If both partners carry the thalassemia trait, their chance of having a child with the fatal homozygous form is 25 percent. Since sickle cell thalassemia and hemoglobin C thalassemia also can be severe, individuals who carry these traits should be made aware of the risk their offspring have of developing disease.

HEMOGLOBINOPATHIES

The homozygous state of hemoglobinopathies is usually recognized early in life. The heterozygous state, however, is usually asymptomatic and may be discovered through routine testing. Microcytosis is common, and distinct morphologic changes such as the sickle cell may be noted. Diagnosis is confirmed by hemoglobin electrophoresis. Hemoglobin S and hemoglobin C are common in African Americans and people of Mediterranean origin. Hemoglobin E is found in 10 percent of southeast Asians. Hemoglobin D is common in natives of some parts of India.

LEAD TOXICITY

Lead poisoning is most common in children, but it also occurs occasionally in adults as a result of occupational exposure to lead. Occupations associated with lead exposure are listed in Table 7.[12] The U.S. Preventive Services Task Force recommends screening children at risk for lead poisoning, including those in older homes who may be exposed to lead paint, those whose parents may be occupationally exposed and those who live near busy highways or hazardous waste dumps.

Adapted from Chao J, Kikano GE. Lead poisoning in children. Am Fam Physician 1993;47:113-20.

Clinical features of lead intoxication include abdominal pain and neuropsychiatric symptoms, but these occur late in the disease and are often nonspecific. If toxicity is suspected, a blood lead level should be taken. In children, lead levels above 10 mg per dL (0.50 mmol per L) are considered abnormal by the newer, more significant Centers for Disease Control and Prevention guidelines, and levels over 44 mg per dL (2.10 mmol per L) may require therapy with chelating agents. Levels above 10 mg per dL (0.50 mmol per L) can induce iron deficiency necessitating iron replacement therapy.[13]

SIDEROBLASTIC ANEMIA

Sideroblastic anemia is a rare cause of microcytic anemia. It is a heterogeneous group of disorders characterized by ineffective erythropoiesis and ringed sideroblasts seen on bone marrow biopsy.[7] Lactate dehydrogenase levels are often elevated, and the peripheral blood smear may show a dimorphic RBC population with both normochromic and hypochromic cells. Causes include congenital sideroblastic anemia, which is probably benign, and acquired sideroblastic anemia, which is further classified as idiopathic or drug induced. Idiopathic causes of sideroblastic anemia include preleukemic syndromes and pyridoxine-responsive anemias. Drugs known to cause sideroblastic anemia include certain antituberculin drugs, chloramphenicol (Chloromycetin), alcohol and various agents used in chemotherapy.[14]

REFERENCES

[1.] Lindenbaum J. Hematologic diseases. An approach to the anemias. In: Wyngaarden JB, Smith LH, Bennett JC, eds. Cecil textbook of medicine. 19th ed. Philadelphia: Saunders, 1992:822-31.

[2.] Iron deficiency in the United States. JAMA 1968; 203:119-24.

[3.] Lee GR, Gardner HJ. Anemia. In: Rakel RE, ed. Textbook of family practice. 3d ed. Philadelphia: Saunders, 1984:1082-91.

[4.] Wintrobe MM, Lukens JN, Lee GR. Disorders of red cells. The approach to the patient with anemia. In: Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN, eds. Wintrobe's clinical hematology. 9th ed. Philadelphia: Lea & Febiger, 1993:715-44.

[5.] Thompson WG, Meola T, Lipkin M Jr, Freedman ML. Red cell distribution width, mean corpuscular volume, and transferrin saturation in the diagnosis of iron deficiency. Arch Intern Med 1988;148:2128-30.

[6.] Guyatt GH, Oxman AD, Ali M, Willan A, McIlroy W, Patterson C. Laboratory diagnosis of iron-deficiency anemia: an overview [Published erratum appears in J Gen Intern Med 1992;7:423]. J Gen Intern Med 1992;7:145-53.

[7.] Massey AC. Microcytic anemia. Differential diagnosis and management of iron deficiency anemia. Med Clin North Am 1992;76:549-66.

[8.] Beissner RS, Trowbridge AA. Clinical assessment of anemia. Postgrad Med 1986;80(6):83-95.

[9.] Oski FA. Iron deficiency in infancy and childhood. N Engl J Med 1993;329:190-3.

[10.] Lops VR, Hunter LP, Dixon LR. Anemia in pregnancy. Am Fam Physician 1995;51:1189-97.

[11.] Waterbury L. Anemia. In: Barker LR, Burton JR, Zieve PD, eds. Principles of ambulatory medicine. 2d ed. Baltimore: Williams & Wilkins, 1986:577-92.

[12.] Bunn FH. Disorders of hemoglobin. In: Isselbacher KJ, Braunwald E, Wilson JD, et al., eds. Harrison's principles of internal medicine. 13th ed. New York: McGraw-Hill, 1994:1734-43.

[13.] Samuels-Reid JH. Anemia. Home Study Self-Assessment Program. No. 150. Kansas City, Mo.: American Academy of Family Physicians, 1991.

[14.] Chao J, Kikano GE. Lead poisoning in children. Am Fam Physician 1993;47:113-20.

The Author

JAMES W. SHINE, M.D. is a clinical assistant professor of family medicine at East Tennessee State University James H. Quillen College of Medicine, Johnson City, and is in rural private practice in Mountain City, Tenn. He received his medical degree from the University of Alabama School of Medicine, Birmingham, where he also served a residency in family practice.

Address correspondence to James W. Shine, M.D., P.O. Box 738, Mountain City, TN37683.

Each year members of a different family practiced department develop articles for "Problem-Oriented Diagnosis." This is the fifth in a series coordinated by the Department of Family and Community Medicine at the University of Alabama at Birmingham. Guest editors of the series are T. Michael Harrington, M.D., and Myra A. Crawford, Ph.D.

COPYRIGHT 1997 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group