Normocytic Anemias
Anemias in which the MCV is 80 to 100 femtoliters.
Normocytic anemia is often worrisome in the elderly. Although it may be caused by obvious concurrent illness (anemia of chronic disease), this type of anemia can also indicate life-threatening conditions, such as multiple myeloma, hemolysis, and myelofibrosis (see Table 69-1).
Anemia of Chronic Disease
Anemia of chronic disease is the most common normocytic anemia in the elderly, accounting for up to 10% of anemias in this population. The most common and most important causes are chronic infection or inflammation, cancer, renal insufficiency, chronic liver disease, endocrine disorders, and malnutrition. The diagnosis is made by excluding other causes of anemia and by finding a chronic disease process.
Chronic infection or inflammation commonly produces anemia, usually after 4 to 8 weeks of illness. The anemia is usually mild and normochromic-normocytic but may be slightly microcytic and hypochromic. It probably results from slightly decreased erythropoietin production, decreased RBC survival, and impaired delivery of iron from the reticuloendothelial system to the bone marrow. The reticulocyte count is low, serum iron and TIBC are normal or reduced, and serum ferritin is normal or elevated. When the underlying disorder is treated, the anemia disappears.
Renal insufficiency produces anemia resulting from decreased erythropoiesis and decreased RBC survival, which are caused by decreased erythropoietin production. Serum iron stores are normal. The anemia occurs independent of nutritional deficiencies common in renal disease (eg, iron or folate deficiency). In hemodialysis patients, injections of erythropoietin correct the anemia. In nondialysis patients, erythropoietin may not completely reverse the anemia, because erythropoietic inhibitors can accumulate. Erythropoietin is given IV to hemodialysis patients and subcutaneously or IV to nondialysis patients with renal failure. The starting dosage is 50 to 100 U/kg 3 times/week, although single weekly doses are now commonly prescribed. The target Hct is 30 to 33%. The maximum recommended dosage is 300 U/kg 3 times/week. Newer studies show that subcutaneous doses are often preferred because, although peak levels are lower, the kinetics are different, leading to more prolonged bone marrow stimulation even with lower doses. This can be an important cost-saving approach, especially in patients who require long-term use of erythropoietin.
Chronic liver disease results in decreased RBC production and survival and produces a normochromic-normocytic or a normochromic-macrocytic anemia. Large quantities of alcohol are toxic to the bone marrow as well as to the liver. Unless liver disease is complicated by bleeding, TIBC is decreased and serum iron is increased, resulting in an increased transferrin saturation. Serum ferritin is also increased and often reflects total body iron overload. Treatment must be directed toward the underlying liver disorder.
Endocrine disorders (eg, pituitary insufficiency, adrenal insufficiency, hypothyroidism) commonly produce a normochromic-normocytic anemia. Unless a specific deficiency of iron, vitamin B12, or folate is identified, treatment focuses on the underlying disorder.
Malnutrition results in an anemia due to deficiency of essential nutrients, such as folic acid, vitamin C, trace minerals (eg, copper), and essential amino acids. In malnutrition, Hb synthesis and RBC production decrease, as does all other protein synthesis (eg, prealbumin and albumin in the liver) and cell (lymphocyte) and fibroblast production.
Anemia Caused by Malignancy
Cancer in its later stages is almost always accompanied by anemia of chronic disease. Frequently, there is no correlation between the degree of anemia and the extent of the tumor. Poor nutrition can lead to calorie, protein, and vitamin deficiency.
Cancer can also cause other types of anemia; eg, bleeding from GI or genitourinary tract tumors or from vascular lesions of the skin can cause iron deficiency anemia. In some cancers there is a microangiopathic hemolytic anemia; in others, splenomegaly leads to increased RBC destruction. Replacement of normal marrow by a neoplasm is a relatively uncommon cause of normochromic-normocytic anemia.
Bone marrow invasion by cancer is often associated with the release of immature leukocytes and nucleated erythrocytes, but the extent of bone marrow metastases correlates poorly with the degree of anemia. Serum iron, vitamin B12, and folate values are normal or elevated, and the ESR is usually elevated.
Hemolytic Anemias
Acquired hemolytic anemia (ie, hemolysis not resulting from a congenital abnormality of the RBCs) increases in incidence with age.
Etiology
Idiopathic autoimmune hemolysis may result from warm-reactive antibodies of the IgG class; from cold agglutinins that are usually of the IgM class but that may be of the IgG class; or from a nonagglutinating cold-activated hemolysin of the IgG class. Idiopathic cold-agglutinin disease occurs primarily in old age.
Secondary immune hemolysis occurs in a wide variety of illnesses. About 30% of secondary immune hemolytic anemias are caused by lymphoproliferative diseases, including chronic lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, and multiple myeloma. Agnogenic myeloid metaplasia, systemic lupus erythematosus, viral infections, Mycoplasma pneumoniae infection, syphilis, and various nonhematologic malignancies are also associated with immune hemolytic anemia.
Drug-induced hemolysis is another major cause of hemolytic anemia. The elderly are prone to this problem because they generally take more drugs than younger persons. Three types of drug-induced hemolysis have been described (see Table 69-2).
Some drugs cause autoantibody formation with antibodies directed against normal RBC antigens. Methyldopa creates these antibodies in 10 to 40% of persons taking it. These antibodies attach to the RBC, resulting in a positive direct Coombs' test result against IgG; however, < 1% of those taking methyldopa actually develop hemolysis. Other drugs that commonly produce autoantibodies but rarely produce autoimmune hemolysis include l-dopa and procainamide. Discontinuing the drug usually corrects the anemia, but autoantibodies may persist for months to years.
Other drugs bind to the surface of the RBC, acting as a hapten. Antibodies, usually IgG, are produced against the drug-RBC complex. The direct Coombs' test result is positive, and if the drug is added to test RBCs, the indirect Coombs' test result is also positive. The anemia clears quickly when the drug is discontinued.
Still other drugs stimulate the production of antibodies to the drug. Drug-antibody immune complexes form in the circulation and bind briefly to the RBC. Hemolysis occurs because the complex activates complement on the RBC surface. The Coombs' test result is positive for complement but not for IgG. Hemolysis ceases quickly when the drug is withdrawn.
Microangiopathic hemolytic anemia (traumatic hemolytic anemia) is commonly caused by obstruction of the microvasculature. Chronic forms may be due to diabetes mellitus, atherosclerosis, or collagen-vascular diseases. A similar anemia occurs in persons with mechanical heart valves, particularly if the valves are malfunctioning. The peripheral blood smear shows fragmented cells (schistocytes).
Acute forms of microangiopathic hemolytic anemia occur in persons with malignant hypertension, vasculitis, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura.
Diagnosis
Increased peripheral destruction of RBCs results in increased production of immature RBCs by the bone marrow, producing an elevated reticulocyte count and polychromatophilia on the peripheral blood smear. If the reticulocytosis is marked, the RBC indices may become macrocytic, because reticulocytes are larger than mature RBCs. Destruction of RBCs results in increased serum levels of unconjugated bilirubin, aspartate transaminase, and lactic dehydrogenase; decreased serum haptoglobin; and increased urine urobilinogen. If hemolysis is intravascular, urine hemosiderin increases. The direct antiglobulin (Coombs') test is used to detect antibody or complement on the RBC and can also identify the antigen to which the antibody is reacting.
Treatment
All hemolytic anemias require folic acid treatment, because this vitamin is used up with the increased bone marrow production of erythrocytes.
Idiopathic autoimmune hemolysis secondary to warm-reactive antibodies of the IgG class responds, in about 75% of cases, to corticosteroid therapy. Prednisone 60 mg/day in divided doses is given initially, although occasionally 100 mg/day is needed. A rise in Hb and Hct and a drop in the reticulocyte count usually occur within 3 to 14 days, but the response may be delayed up to 8 weeks. After remission, the dosage may be tapered by 5 mg/week. A relapse requires increasing the dosage by 15 to 20 mg/day, followed by a more gradual tapering. Some patients continue to need a small daily dose or alternate-day therapy for months or even years.
If after 4 to 8 weeks, prednisone produces no response, higher doses may be tried or 200 mg bid to qid of danazol (an androgen) may be added. If this fails, the next step is usually splenectomy, which achieves long-term remission in 50 to 75% of cases. In patients who do not respond to these measures or who are poor surgical candidates, immunosuppressants (cyclophosphamide 150 mg/day or azathioprine 200 mg/day) may be useful.
Transfusion is rarely used to treat warm-antibody autoimmune hemolysis except in those patients with severe symptoms of anemia. Blood compatibility testing is problematic, and the autoantibodies reduce the survival of the transfused RBCs. Plasmapheresis is usually not successful, because IgG has a large volume of distribution in the body.
Idiopathic cold-agglutinin disease is treated by avoiding exposure to cold. If transfusion is necessary, it should be performed with warmed, washed RBCs. Plasmapheresis may lead to temporary improvement, because IgM is confined to the intravascular space. Corticosteroids and splenectomy are seldom helpful.
Secondary immune hemolysis usually improves only with treatment of the underlying illness. If this approach is not possible, treatment may be tried as described above for idiopathic disease, but success is less likely.
Drug-induced hemolysis is usually treated by simply discontinuing the responsible drug. In rare cases, methyldopa-induced autoimmune hemolysis continues long enough to require corticosteroid therapy, as described above for idiopathic autoimmune hemolysis.
Microangiopathic hemolytic anemia is treated by correcting the underlying disease process. Management includes treatment with iron to replace the loss in the urine, which occurs only with intravascular hemolysis. In the extravascular hemolytic anemias, iron is conserved and recycled via the reticuloendothelial system.
Aplastic Anemia
This normochromic-normocytic anemia results from decreased bone marrow production of RBCs alone (pure RBC aplasia) or of all cell lines. Aplastic anemia is not very common, but its incidence increases with age. In this disorder, the reticulocyte count is low; serum levels of iron, vitamin B12, and folate are normal; and the bone marrow is hypoplastic. If thrombocytopenia occurs, bleeding may become a problem. The overall mortality rate is > 50%.
Idiopathic aplastic anemia is usually a disease of adolescents and young adults but can occur in old age. The most common pathogenesis involves T-cell-mediated suppression of the hematopoietic stem cell. Secondary aplastic anemia can be caused by chemicals, radiation, or drugs, especially chemotherapeutic drugs, chloramphenicol, gold, and anticonvulsants (see Table 69-3). Thymoma and chronic lymphocytic leukemia sometimes cause pure RBC aplasia.
Treatment
All potentially causative drugs must be discontinued. An oral androgen (eg, oxymetholone 1 to 2 mg/kg/day) may be given but is rarely successful. Bone marrow transplantation, the only curative therapy, usually is not an option in patients > 65, who can rarely tolerate it. Ongoing supportive treatment with transfusions is, therefore, required. Pure RBC aplasia may respond to prednisone or cyclophosphamide; if it is associated with thymoma, tumor resection may be helpful. Usually, attempts are made to suppress cellular immunity with cyclosporine or high doses of antithymocyte immunoglobulins. The use of corticosteroids is controversial. Recombinant human granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interleukin-3, erythropoietin, and thrombopoietin may be useful.
Anemia of Primary Autonomic Failure
This rare normochromic-normocytic anemia occurs in 38% of elderly patients with primary autonomic dysfunction (Shy-Drager syndrome) and appears to be caused by reduced erythropoietin secretion. A dilutional effect on Hb concentration from fluid overload may also be a factor. Erythropoietin levels are low in the absence of renal disease, and no other cause of anemia is present. In about 80% of these cases, the anemia is corrected with low-dose erythropoietin treatment (50 U/kg 3 times/week).
Sideroblastic Anemias
Sideroblastic anemias are a heterogeneous group of disorders characterized by impaired heme synthesis. Iron continues to go into the mitochondria of the bone marrow erythroblasts, but since heme is not being synthesized, the iron accumulates and ultimately damages the mitochondria and the cell, resulting in ineffective erythropoiesis. Ringed sideroblasts can be seen in bone marrow stain for iron; they represent iron in the mitochondria that encircle the nucleus of the erythroblast. Eventually, this iron accumulation leads to an iron overload in the body.
Sideroblastic anemias may be primary or secondary to other conditions. The primary genetic form usually is diagnosed in younger people. The primary acquired form is often a myelodysplastic syndrome in elderly people. Chronic alcohol use is probably the most common cause of a secondary sideroblastic anemia. Sideroblastic anemias also occur secondary to hematologic malignancies (eg, multiple myeloma, acute leukemias); vitamin B12 and/or folate deficiencies; rheumatic disorders; use of drugs that inhibit heme synthesis (eg, phenytoin, isoniazid, chloramphenicol); and exposure to toxins, especially lead.
In sideroblastic anemias, the MCV may be low, normal, or high, but the reticulocyte count is always low. Serum iron, transferrin saturation, and ferritin levels are high. A hypochromic anemia in an elderly person without iron deficiency is usually a sideroblastic anemia. In bone marrow examination, there is usually erythroid hyperplasia, and 15% of erythroid cells are ringed sideroblasts.
Any possibly offending drug should be stopped, and any underlying disorders should be treated. Any nutritional disorder should also be treated. If there is no response, pyridoxine 200 mg/day should be given for 1 to 2 months. If there is still no response, transfusions may be required if the anemia is severe (Hb < 8 g/dL) or if the patient is symptomatic from the anemia.
Other Causes of Anemia
A mild normochromic-normocytic anemia without any underlying disease or deficiency (Hb usually between 11 and 12 g/dL) has been reported in people > 70, accounting for up to 30% of the normochromic-normocytic anemias in this age group. The bone marrow does not contain ringed sideroblasts. Unexplained anemia may be associated with low neutrophil, lymphocyte, and platelet counts and with increased RBC 2,3-diphosphoglycerate levels, implying that this condition is not merely a normal age-related variant. Its significance is unknown, but it is probably a myelodysplastic syndrome, even though there are no ringed sideroblasts in the bone marrow.
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