Anemia, Sideroblastic

Anemia in the Elderly Controversy exists about the occurrence of an age-related decline in hematologic parameters. The etiology of anemia in elderly patients is often confounded by chronic and inapparent disease. The diagnosis is assisted by knowledge of the clues to the causes of hypoproliferative anemia, ineffective hematopoiesis and hemolysis. Anemia is the most common hematologic disorder in elderly patients. A problem in developing an approach to anemia in elderly patients is one of definition. In standard hematology textbooks, anemia is defined as a low quantity or quality of circulating erythrocytes.(1) What constitutes "normal" for elderly patients is a matter of considerable debate. The World Health Organization (WHO) recommended in 1968 that a cutoff hemoglobin value of 13 g per dL (130 g per L) for men and 12 g per dL (120 g per L) for women be used for the diagnosis of anemia.(2) The original critical hemoglobin value of 14 g per dL (140 g per L) for men, as specified by WHO in 1959, was lowered to 13 g per dL (130 g per L) because community surveys had documented a high prevalence of low-grade anemia in elderly men when the cutoff value of 14g per dL (140g per L) was used.(3,4)

Is Anemia Age-Related?

There is controversy in the geriatric and hematologic literature about whether an age-related decline in hematologic parameters occurs. Proponents of this concept believe that hematologic norms should be lowered for elderly patients.(5,6) Opponents contend that while anemia is prevalent in the elderly, it should not be regarded as a normal concomitant of the aging process.(7,8) Opponents caution against the establishment of lower hematologic norms for elderly patients and recommend that a careful search for an underlying cause of anemia be performed.(9) The difficulty in defining normal hematologic values for elderly patients lies in the fact that studies of elderly populations have included large numbers of people with chronic but often inapparent underlying disease that may affect hematopoietic function.(10)

A study of carefully selected elderly patients, in which the subjects were screened for health status, socioeconomic status, race, nutritional status and altitude of where they were living, revealed that 0 percent of the elderly women had hemoglobin values less than 12 g per dL (120 g per L) and 2.3 percent of the elderly men had values less than 14 g per dL (140 g per L).(11) A study of healthy, very old people revealed that little fluctuation in hemoglobin values occurs even into the ninth decade.(12)

Conversely, in another study,(13) 34 percent of the elderly men and 21 percent of the elderly women had hemoglobin values less than 14 g per dL (140 g per L) and 12 g per dL (120 g per L), respectively. Of these patients, only 10 percent had a readily identifiable cause of anemia (three patients had iron deficiency anemia and two patients had anemia of chronic disease). The high prevalence of anemia in this study may have been because these patients came from lower socioeconomic groups.

In 1984, Lipschitz and colleagues(14) reported on a study that included 196 healthy elderly men. Thirty-eight (19.4 percent) had hemoglobin values less than 13 g per dL (130g per L). The cause of anemia could be identified in only 12 (32 percent) of these men. Hematopoietic studies in the group of anemic men, compared with a group of healthy men and a group of younger healthy patients, showed that there was a significant reduction in the committed cell lines of the erythrocyte series (colony-forming unit-erythrocyte [CFU-E]). The most primitive red cell precursors, the burst-forming unit-erythrocyte (BFU-E), were not reduced in numbers in the elderly anemic men. The authors concluded that basal hematopoietic function was not impaired in this group of elderly anemic men. A disorder of hematopoiesis appeared to underlie the anemia. Postulated causes for the impaired hematopoietic function included chronic low-grade nutritional deficiency or chronic low-grade disease that had not yet become apparent.

Screening for Anemia

These studies suggest that in otherwise healthy elderly people, anemia is not normal. There does, however, appear to be a group of elderly people who have low-grade anemia, the etiology of which is unclear. The yield from a conventional work-up in these patients is extremely low.

In high-risk groups, however, screening for anemia is likely to bear dividends. These groups include hospitalized patients, institutionalized patients, persons of lower socioeconomic classes, blacks,(15) patients with concomitant disease or poor nutritional status, postgastrectomy patients and elderly men.

Elderly patients can be classified as having a high, moderate or low risk of significant anemia in association with a given hemoglobin value.(16,17) Men can be considered at high risk if they have a hemoglobin level under 12 g per dL (120 g per L), at moderate risk if the value is 12 to 14 g per dL (120 to 140 g per L), and at low risk if the value is above 14 g per dL (140 g per L). Elderly women can be considered at high risk if the hemoglobin level is less than 10 g per dL (100 g per L), at moderate risk if it is 10 to 12 g per dL (100 to 120 g per L), and at low risk if the hemoglobin is above 12 g per dL (120 g per L). Using these risk categories, 6 to 10 percent of elderly women and 15 percent of elderly men will be at moderate risk for anemia. Only 1 to 2 percent of elderly men and women will be at high risk for anemia.

Anemia in the elderly population may be classified into three types: (1) disorders associated with decreased red cell production (the hypoproliferative anemias); (2) disorders associated with ineffective hematopoiesis (the megaloblastic anemias, in which there is an abnormality of nuclear maturation, and the thalassemias and sideroblastic anemias, in which the abnormality occurs at a cytoplasmic maturation level), and (3) disorders associated with decreased red cell survival time (the hemolytic anemias).(17)

Hypoproliferative Anemias

There are three groups of hypoproliferative anemias. One type is the result of reduced iron supply for hemoglobin synthesis, which occurs from blood loss, chronic inflammation or malnutrition. Another cause of hypoproliferative anemia is decreased red cell production due to reduced erythropoietin stimulus, such as in renal disease and hypothyroidism. Finally, red cell production can be affected by a marrow defect, which may occur secondary to drugs, fibrosis or tumor.

An inadequate iron supply for hemoglobin synthesis is the most common cause of hypoproliferative anemia. This usually occurs secondary to blood loss, but may also occur in chronic disease states where iron is inadequately mobilized from the reticuloendothelial system. Malnutrition is an uncommon cause of inadequate iron supply.

IRON METABOLISM IN THE ELDERLY

Iron requirements do not change with aging. Western diets contain an estimated 5 g of iron per 1,000 calories, of which 10 percent is absorbed.(18) There is no evidence to suggest that iron absorption is impaired in elderly people.(19) While inorganic iron absorption may be reduced in patients with atrophic gastritis and hypochlorhydria, organic iron or heme iron is well absorbed even in these conditions. Tea and coffee consumption reduce iron absorption, while vitamin C enhances absorption. Iron absorption is increased in people of all ages when any reduction occurs in total body iron stores.(20)

Iron storage in the form of ferritin and hemosiderin increases linearly with age. Total body iron averages 3.5 to 5 g, of which 66 percent is in the circulating hemoglobin form. Iron loss is minimal in elderly people; less than 1 g per day is lost in stool, sweat, urine and other secretions. It is unusual for iron deficiency to occur from dietary deficiency alone.

If iron deficiency is found, then a search for a source of bleeding is mandatory. Nonsteroidal anti-inflammatory drugs and steroids commonly precipitate gastrointestinal bleeding in elderly patients. Carcinoma of the gastrointestinal tract may be another cause of occult blood loss, as may angiodysplasia of the colon. In many instances, however, the site of blood loss is not identified in elderly patients.

Laboratory diagnosis of iron deficiency anemia may be difficult in elderly patients.(21) In the early stages of iron depletion without anemia, the only indicator of iron deficiency may be a reduced serum ferritin concentration. As iron depletion progresses to iron deficiency, a low transferrin saturation and slight microcytosis may be seen. This stage is also characterized by an increased concentration of free erythrocyte protoporphyrin and very reduced, to almost absent, marrow iron stores. The full-blown picture of iron deficiency anemia is the final stage, characterized by a low transferrin saturation (less than 16 percent), a low serum ferritin level (less than 12 ng per mL [12 micro g per L]), an elevated free erythrocyte protoporphyrin level, absent marrow iron stores and hypochromic microcytic anemia.

The blood picture of iron deficiency anemia may be altered in elderly patients with chronic diseases.(22) These patients may have normal to high ferritin levels, low serum iron concentrations and low transferrin levels. When iron deficiency anemia and chronic disease coexist, the only definitive test may be bone marrow examination.

Patients with a low-grade anemia may benefit from a trial of iron therapy. Patients with iron deficiency will show improvement within a few weeks. No response will occur in patients with chronic inflammatory disease but no iron deficiency. A 2 g per dL (20 g per L) rise in hemoglobin should occur within three weeks of the initiation of therapy. Iron supplementation should be continued for six months to replenish iron stores.

Gastrointestinal side effects are common in elderly patients taking oral iron preparations. If side effects are too bothersome, it may be necessary to administer iron therapy with food, even though absorption will be reduced. Pediatric suspensions are sometimes well tolerated. Parenteral iron therapy should be reserved for those patients with refractory side effects or with low-grade blood loss that exceeds the ability to replace iron orally.

ANEMIA OF CHRONIC DISEASE

Inadequate iron supply for hematopoiesis also underlies the low-grade anemia that occurs in association with chronic diseases in which mobilization of iron and incorporation of iron into hemoglobin is impaired.(23) Disorders that may lead to anemia include chronic infections, bed sores, neoplasms, collagen vascular disease, protein malnutrition, vitamin C deficiency, endocrine disorders and renal failure.

Several mechanisms have been postulated for the development of anemia in these conditions.(22) Ferrokinetic studies have shown that the release of reticuloendothelial iron to the erythroblast is decreased, although the mechanism for this abnormality is unknown. This situation is compounded by a reduction in erythropoietin production relative to the degree of anemia. Other mechanism may play a role, depending on the associated condition. A moderate reduction in red cell survival occurs in chronic renal disease. Blood loss, immune hemolysis and sideroblastic anemia will further contribute to the development of anemia in these conditions.

The anemia of chronic disease is usually mild, not progressive, and is related to the severity of the disease.(24) Typically, the red cells are normochromic and normocytic, although occasionally they are microcytic. The serum iron level is usually low, as is the serum transferrin level. Transferrin saturation is often normal but may be low. Serum ferritin is usually normal or increased. Bone marrow examination reveals abundant reticuloendothelial iron, but no iron is in the erythroblasts.

A disorder that may present as an anemia of chronic disease is multiple myeloma.(25) Elderly patients may manifest a low-grade normochromic normocytic anemia. A high level of suspicion must be maintained to make this diagnosis. The combination of anemia, fatigue and elevation of the erythrocyte sedimentation rate (ESR) should prompt the clinician to order serum protein electrophoresis.

Ineffective Erythropoiesis

MEGALOBLASTIC ANEMIAS

In elderly patients, the cardinal features of the megaloblastic anemias, almost exclusively due to vitamin B12 or folate deficiency, are macrocytosis (MCV greater than 110), hypersegmented granulocytes, indirect hyperbilirubinemia and a bone marrow that shows megaloblastoid erythrocyte precursors and giant metamyelocytes. Normoblastic macrocytosis may be found in elderly patients who have been chronic tobacco users or chronic alcohol abusers.(26) Hypothyroid patients, patients with leukemia and patients taking certain medications (typically anticonvulsants) may have normoblastic macrocytosis.

VITAMIN B12 DEFICIENCY

Low vitamin B12 levels may be present in elderly patients without any hematologic or neurologic complications.(27) The significance of this abnormality is unclear. Low vitamin B12 levels may accompany iron deficiency anemia or folate deficiency, even when B12 stores are normal. Drugs that interfere with bacterial growth may cause false-low levels when vitamin B12 is assayed in vitro.

Vitamin B12 is present in most animal tissues but not in plants. A normal diet contains 5 to 30 micro g per day; 2 micro g can be absorbed from a single meal, since this amount is the limit for ileal receptor sites.(28) Vitamin B12 loss is approximately 1 to 12 micro g per day, but the loss is proportional to the size of the total vitamin B12 pool. Loss occurs at a daily rate of approximately 0.1 to 0.2 percent of the pool. Elderly patients show no evidence of an inability to absorb vitamin B12, nor do they have any evidence of vitamin B12 storage depletion. Ninety percent of vitamin B12 is stored in the liver. It is estimated that depletion of vitamin B12 stores would take three to six years in patients with pernicious anemia and ten to 20 years if the diet were deficient in this vitamin.

Vitamin B12 deficiency is rare, but its prevalence increases with age. The most common etiology is pernicious anemia. However, atrophic gastritis, small bowel bacterial overgrowth, ileal malfunction and certain drugs may also cause B12 deficiency.

PERNICIOUS ANEMIA

Pernicious anemia is a systemic disease characterized by megaloblastic hematopoiesis or neuropathy, or both. It is a disease of old age, with a peak incidence in persons over age 60. Over the age of 70 years, 0.1 to 0.2 percent of the population are affected. Pernicious anemia is especially prevalent in people of northern European descent and more prevalent in persons with blood group type A. It is a disorder with familial and autoimmune etiologic components. Antibodies are directed against gastric parietal cells and intrinsic factor. These antibodies specifically prevent vitamin B12 binding to intrinsic factor and reduce intrinsic factor synthesis and secretion by causing parietal cell atrophy.

Clinically, patients with pernicious anemia present with fatigue, reduced drive and anorexia. Other common symptoms include sore tongue and mouth. Some patients present with weight loss. Neurologic involvement is variable. Any combination of neurologic symptoms is possible, but common symptoms include paresthesias, gait abnormalities, impotence, visual problems, urinary incontinence, sensory ataxia and peripheral neuropathy. The diagnosis is made by the Schilling test, which demonstrates malabsorption of radioactive-labeled cyanocobalamin.

Vitamin B12 malabsorption can be corrected with the addition of intrinsic factor in the form of intramuscular hydroxocobalamin (alphaRedisol). Therapy must be continued for life. Hematopoiesis improves almost immediately, but neurologic symptoms rarely improve if they have been present for more than six months. The incidence of concomitant hypothyroidism and other autoimmune conditions is high in patients with pernicious anemia. In addition, 5 to 8 percent of patients with pernicious anemia develop gastric carcinoma over the ensuing 15 to 20 years.(29)

Atrophic gastritis occurs in up to 80 percent of people over the age of 60. These patients rarely develop pernicious anemia; in one study,(30) two (1.7 percent) of 116 patients developed pernicious anemia after 23 years of follow-up. Very little intrinsic factor is required to absorb vitamin B12. Patients with atrophic gastritis usually secrete enough intrinsic factor to allow adequate absorption of vitamin B12.

Rarely, small bowel bacterial overgrowth or ileal malfunction interferes with vitamin B12 absorption. Drugs that may impair absorption include neomycin, ethanol and potassium chloride.

FOLIC ACID DEFICIENCY

Folic acid is found in fresh green vegetables, nuts, yeast and liver. The minimum requirement in adults is 100 micro g per day. Folate absorption occurs in the upper small intestine.

Low serum folate levels are common in the elderly, but serum levels do not always reflect the storage status of folic acid. Folic acid stores will be depleted in four months if dietary sources are insufficient, which may be a problem in elderly patients. Megaloblastic anemias secondary to folate deficiency are uncommon in elderly patients.(31) In community surveys, the incidence of folate deficiency anemia is very low or nonexistent.

Alcoholic elderly patients are particularly prone to folic acid deficiency.(32) This usually occurs on a dietary basis, but alcohol has a direct toxic effect on bone marrow and reduces folic acid absorption. Malabsorption may also occur in association with celiac disease and tropical sprue. Folic acid requirements increase in situations where there is increased cell turnover, such as in hemolysis and in certain blood disorders and neoplasms.

Folic acid effectiveness is reduced in vitamin C deficiency states. Vitamin C acts as a coenzyme in folate metabolism. Anticonvulsants, trimethoprim and pyrimethamine may also interfere with folate metabolism.

Clinical features of folate deficiency are nonspecific and include mild confusion, depression, apathy and intellectual loss. Rarely do patients with intellectual loss respond to folate replacement. The diagnosis is made by the demonstration of a low red cell folate concentration. Treatment is with oral folic acid supplements, usually 5 mg per day. Before beginning therapy, it is important to exclude vitamin B12 deficiency since administration of folic acid in a patient with B12 deficiency may induce neurologic complications.

CYTOPLASMIC MATURATION ABNORMALITIES

Abnormalities of cytoplasmic maturation include the sideroblastic anemias, characterized by a disorder of porphyrin metabolism, and the thalassemias, in which hemoglobin chain production is defective.

Sideroblastic anemias are a heterogeneous group of disorders manifested by ineffective erythropoiesis and defective hemoglobin synthesis.(33) The cause usually remains unknown; the pathology is an acquired, as yet undefined abnormality of porphyrin synthesis. Sideroblastic anemia may occur secondary to alcohol use, drugs (in particular, antituberculous drugs) and a number of diseases, including infections, neoplasms (gastrointestinal, renal cell and lymphomas) and inflammatory disorders (rheumatoid arthritis, systemic lupus erythematosus).

The diagnosis of sideroblastic anemia is suggested by the presence of microcytosis on the peripheral blood smear but no evidence of iron deficiency. Serum iron is usually increased, as is serum ferritin. The blood smear may show a dimorphic picture, with microcytic cells and normocytic cells. Other features are poikilocytosis, basophilic stippling and iron-laden red blood cells.

Idiopathic sideroblastic anemia is usually benign and rarely affects survival. A fraction of patients with sideroblastic anemia may respond to therapeutic doses of pyridoxine, which acts as a coenzyme in the first committed reaction of porphyrin synthesis.

Occasionally, patients with sideroblastic anemia may require blood transfusion, usually a poor prognostic sign. Iron replacement and transfusions predispose these patients to iron overload and secondary hemochromatosis. Rarely, patients with sideroblastic anemia may develop leukemia. In this situation, abnormal platelets or white cells are seen on the peripheral smear.

Immunologic Hemolytic Anemia

The third major group of anemias in elderly patients are the hemolytic anemias, although they are not common. Hemolytic anemias are characterized by a shortened red cell survival time. The hallmark on the peripheral blood smear is reticulocytosis. There are three major types of hemolytic anemia: (1) immunologic, (2) intrinsic red cell membrane defects, abnormal hemoglobins or red cell enzyme defects and (3) extrinsic mechanical or lytic factors, all of which reduce the red cell life span.

Immunologic hemolytic anemia may occur on an autoimmune basis. Autoantibodies may be warm-reacting (IgG) or cold-reacting (IgM or, more rarely, IgG). The etiology is usually idiopathic. The Coombs' test is usually positive. Autoimmune hemolytic anemia may develop in association with malignant lymphomas, myelofibrosis, paraproteinemias, collagen disease and ulcerative colitis. Warm or cold antibodies may be present in these situations.

Immunologic hemolytic anemia may also occur secondary to use of medications, most often methyldopa (Aldomet).(34) Less than 0.1 percent of patients treated with methyldopa will develop hemolytic anemia, although up to 15 percent will have positive Coombs' tests. Drug-induced hemolytic anemia also may occur in patients receiving high doses of penicillin or cephalosporins. Occasionally, quinidine and phenacetin will induce an autoimmune hemolytic anemia. Many other medications have been implicated as causative agents for hemolysis.

Other causes of hemolytic anemia, such as intrinsic membrane defects, enzyme defects or abnormal hemoglobins, are extremely uncommon in elderly patients. Prosthetic heart valves may cause low-grade mechanical hemolysis.

Treatment of hemolytic anemia is difficult and may include steroids, immuno-suppression and, occasionally, splenectomy. Hematologic consultation is usually indicated.

Final Comment

Although common in elderly patients, anemia is not a normal concomitant of the aging process. The etiology of anemia is usually multifactorial in elderly patients. Low-grade reduction in the hemoglobin value is common in elderly patients, but the work-up for moderate anemia is often unrewarding. In high-risk patients, such as men with hemoglobin values less than 12 g per dL (120 g per L) and women with hemoglobin values less than 10 g per dL (100 g per L), the yield is higher and a thorough search for the cause of anemia should be undertaken. REFERENCES (1)Britton CJ. Disorders of the blood: diagnosis, pathology, treatment, technique. 10th ed. London: Churchill, 1969:159. (2)World Health Organization. Nutritional anaemias: report of a WHO scientific group. Technical report series, no. 405. Geneva: World Health Organization, 1968. (3)Williamson J, Stokoe IH, Gray S, et al. Old people at home: their unreported needs. Lancet 1964;1(7343):1117-20. (4)Myers AM, Saunders CR, Chalmers DG. The haemoglobin level of fit elderly people. Lancet 1968;2(562):261-3. (5)Earney WW, Earney AJ. Geriatric hematology. J Am Geriatr Soc 1972;20:174-7. (6)Smith JS, Whitelaw DM. Hemoglobin values in aged men. Can Med Assoc J 1971;105:816-8. (7)Lewis R. Anemia--a common but never a normal concomitant of aging. Geriatrics 1976;31(12):53-60. (8)Freedman ML, Marcus DL. Anemia and the elderly: is it physiology or pathology? Am J Med Sci 1980;280(2):81-5. (9)Garry PJ, Goodwin JS, Hunt WC. Iron status and anemia in the elderly: new findings and a review of previous studies. J Am Geriatr Soc 1983;31:389-99. (10)Htoo MS, Kofkoff RL, Freedman ML. Erythrocyte parameters in the elderly: an argument against new geriatric normal values. J Am Geriatr Soc 1979;27:547-51. (11)Fisher S, Hendricks DG, Mahoney AW. Nutritional assessment of senior rural Utahns by biochemical and physical measurements. Am J Clin Nutr 1978;31:667-72. (12)Zauber NP, Zauber AG. Hematologic data of healthy very old people. JAMA 1987;257:2181-4. (13)Lipschitz DA, Mitchell CO, Thompson C. The anemia of senescence. Am J Hematol 1981;11:47-54. (14)Lipschitz DA, Udupa KB, Milton KY, Thompson CO. Effect of age on hematopoiesis in man. Blood 1984;63:502-9. (15)Garn SM, Ryan AS, Owen GM, Abraham S. Income matched black-white hemoglobin differences after correction for low transferrin saturations. Am J Clin Nutr 1981;34:1645-7. (16)Ten-state nutrition survey. Atlanta: Centers for Disease Control, 1970:3-67. (17)Lipschitz DA. Anemia. In: Exton-Smith AN, Weksler ME, eds. Practical geriatric medicine. New York: Churchill Livingstone; 1985:290-6. (18)Exton-Smith AN. Nutrition of the elderly. Br J Hosp Med 1971;5:639-46. (19)Marx JJ. Normal iron absorption and decreased red cell iron uptake in the aged. Blood 1979;53:204-11. (20)Freedman ML. Iron deficiency in the elderly. Hosp Pract [Off] 1986;21(3A):115-22,127,130. (21)Cook JD. Clinical evaluation of iron deficiency. Semin Hematol 1982;19:6-18. (22)Freedman ML. Anemia in the elderly. Compr Ther 1983;9(7):45-53. (23)Hyams DE. The blood. In: Brocklehurst JC, ed. Textbook of geriatric medicine and gerontology. 3d ed. New York: Churchill Livingstone, 1985:835-98. (24)Cartwright GE, Lee GR. The anaemia of chronic disorders. Br J Haematol 1971;21:147-52. (25)Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med 1980;302:1347-9. (26)Powell DE. Macrocytosis in the elderly. Practitioner 1978;221(1322):204-9. (27)Spray GH. The estimation and significance of the level of vitamin B12 in serum. Postgrad Med J 1962;38(1):35-40. (28)Lindenbaum J. Aspects of vitamin B12 and folate metabolism in malabsorption syndromes. Am J Med 1979;67:1037-48. (29)von Knorre G, Pechau KG. [Late fate of patients with pernicious anemia.] Z Gesamte Inn Med 1975;30:701-6. (30)Siurala M, Lehtola J, Ihamaki T. Atrophic gastritis and its sequelae. Results of 19-23 years' follow-up examinations. Scand J Gastroenterol 1974;9:441-6. (31)Batata M, Spray GH, Bolton FG, Higgins G, Wollner L. Blood and bone marrow changes in elderly patients, with special reference to folic acid, vitamin B12, iron, and ascorbic acid. Br Med J 1967;2(553):667-9. (32)Wu A, Chanarin I, Slavin G, Levi AJ. Folate deficiency in the alcoholic--its relationship to clinical and haematological abnormalities, liver disease and folate stores. Br J Haematol 1975;29:469-78. (33)Cartwright GE, Deiss A. Sideroblasts, siderocytes, and sideroblastic anemia. N Engl J Med 1975;292:185-93. (34)Petz LD. Drug-induced immune haemolytic anaemia. Clin Haematol 1980;9:455-82.

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