Introduction

Anemia is defined as a hemoglobin level below 13 g/dL (8.07 mmol/L) for men and 12 g/dL (7.45 mmol/L) for women. There is often the impression that anemia of senescence and a mild anemia in elderly is likely to reflect a physiological rather than pathological process. As a result, the timing of the decision to investigate anemia in an elderly person is often controversial.

The prevalence of anemia increases significantly after 75 years of age. Some studies have observed a greater prevalence of anemia amongst the institutionalized elderly.

Table I. Classification of Anemia in the Elderly.

Hypoproliferative	Ineffective	Hemolytic
Intrinsic marrow lesion: - Stem cell dysfunction Aplastic anemia RBC aplasia - Marrow replacement Fibrosis Tumor - Myelophthisic anemia - Mild marrow failure in the elderly (etiology unknown). Erythropoietin Lack: - Renal disease - Nutritional - Endocrine Iron deficient erythropoiesis: - Iron deficiency anemia - Anemia of chronic disease - Inflammation	Megaloblastic - Vitamin B12 deficiency - Folate deficiency Microcytic/Normocytic: - Thalassemia - Myelodysplastic syndrome - Sideroblastic anemia	Immunologic: - Idiopathic - Secondary: Drugs Lymphoma Collagen vascular disease Intrinsic: - Metabolic - Hemoglobinopathy Extrinsic: - Mechanical - Lytic agents

The regulation of erythropoiesis involves a complex series of interactions and a multitude of regulatory cytokines. There are two forms of erythroid progenitor cells -- the burst-forming unit erythroid (BFU-E) and colony-forming unit-erythroid (CFU-E), the immediate precursor of proerythroblasts. The replicative capacity of the bone marrow far exceeds the life expectancy of the animal, though the aged erythropoietic system appears to be more sensitive to external stresses.

Studies have shown that erythropoietin response to anemia is not altered with aging and a true anemia does not occur, so other etiologies must be considered for the anemia prevalent among elderly humans. Recent findings, for example, demonstrate that anemia is extremely rare in very affluent and healthy elderly communities. Anemia is never a normal consequence of advancing age.

After anemia of chronic disease, iron deficiency anemia (IDA) is the most common cause of anemia in the elderly. IDA is important to diagnose because appropriate iron therapy may improve symptoms and inappropriate iron therapy may cause clinically important side effects. IDA in the elderly may be a marker for occult gastrointestinal pathology.

To establish the diagnosis, use less invasive diagnostic tests of iron stores. Iron binding capacity decreases with aging and is affected by factors such as malnutrition and chronic disease, both of which have a higher prevalence in the elderly. Serum ferritin levels increase with aging and may be elevated by acute and chronic inflammatory conditions.

When unexplained IDA occurs in the elderly patient, it is almost exclusively due to blood loss from the intestinal tract, even if the bleeding is not detected by repeated stool guaiac determination. Epistaxis, abnormal bleeding from the uterus and hematuria are rare but easily recognizable causes of blood loss in elderly patients. Causes of gastrointestinal bleeding in the elderly include drugs and neoplasm.

Therapy

Oral Iron: Approximately 30 mg of iron is absorbed upon daily administration of 180 mg of elemental iron. Thus, a standard dosage would be 60 mg of elemental iron three times a day between meals to maximize absorption. However, a single dose a day will produce the same effect in the majority of persons with normal absorption. GI side effects, such as nausea, abdominal cramping, epigastric distress, constipation and/or diarrhea, are noted in approximately 15-20% of patients receiving oral iron supplements. These appear to be dose related. Correction of the anemia usually occurs within six weeks. Reaccumulation of iron stores, to approximately 500 mg, takes at least 4-6 months because of both decreased absorption following correction of the anemia and often continued iron losses. Serum ferritin usually normalized upon correction of iron stores.

Parental Iron Therapy: Indications for parenteral iron therapy include malabsorption, intolerance to oral preparations and iron losses exceeding maximal oral replacement.

Sideroblastic Anemia

Sideroblastic anemia occurs in both inherited and acquired forms. Generally, the acquired form is a disease of older adults and is considered a myelodysplastic syndrome. It is characterized by markedly increased ineffective erythropoiesis associated with increased intestinal absorption. In addition, many patients are transfusion dependent and, therefore, are prone to accumulate excess iron from the transfused red blood cells. The sideroblastic anemias, other than the idiopathic forms, may respond to treatment with pyridoxine. Most patients will have stable anemia and associated symptoms over many years.

Anemia of Chronic Disease (ACD)

ACD is a frequent event in elderly patients, complicating a variety of disorders, including inflammatory processes, malignant diseases and infections. It was reported as the most common type of anemia in hospitalized patients. A major component of ACD is often due to protein energy malnutrition. ACD is associated with decreased serum iron level, decreased transferrin saturation and normal to increased ferritin.

There are three mechanisms involved in the development of ACD: 1) failure of erythropoiesis, 2) lack of iron for hemoglobin synthesis and 3) decreased RBC survival.

The management of ACD must be tailored to the individual patient and the primary disease process. A patient with an acute infection and a mild hypoproliferative anemia can be expected to recover spontaneously as the infection is treated. The same is true for a patient with chronic inflammatory anemia unless the patient is elderly with cardiovascular disease. In this case, judicious transfusion therapy may be necessary to maintain the patient's exercise tolerance and well being.

Megaloblastic Anemia (MA)

Megaloblastic anemia is a descriptive morphologic term that refers to abnormal hematomyelopoiesis, characterized by dyssynchronous nuclear and cytoplasmic maturation in all myeloid and erythroid cell lines. This is the direct result of aberrant DNA synthesis provoked by a single or combined deficiency of either cobalamin (Cbl) or folate. Recent evidence suggests that cobalamin deficiency is much more common in older people than is generally perceived. MA occurs most frequently in patients older than 60 years of age and may be severe.

Animal products are the primary dietary source of cobalamin. Meat contains hydroxy and adenosyl cobalamin and dairy products contain hydroxy and meth cobalamin. The average adult requirement for Cobalamin is approximately 1 mg/d. Intrinsic factor (IF) is required for the absorption of cobalamin in the intestine.

Intracellularly, cobalamin has two enzymatic functions:
1. Methylmalonate - succinate isomerization
2. Methylation of homocysteine to methionine.

Cobalamin deficiency leads to intracellular methionine deficiency, which, theoretically, blocks the availability of reduced folate within the cell. Patients with pernicious anemia have an estimated risk of gastric adenocarcinoma that ranges from three to five times that in the general population. It should be noted that a normal serum cobalamin level does not exclude cobalamin deficiency.

Other important tests for pernicious anemia is to detect the presence of IF antibody (type I which blocks the binding of Vitamin B12 to IF and type II which react with the IF binding site to the ileal receptors). Type I is present in 31-76% of patient with pernicious anemia. The Schilling test is performed to assess the absorption of orally ingested radiolabeled crystalline cyano-cobalamine (1 mg) without (Stage I) and with (Stage II) IF.

Conditions Associated with Abnormal Schilling Test

Abnormal first stage and normal second stage

Pernicious anemia
Congenital intrinsic factor deficiency
Abnormal intrinsic factor molecule
Gastrectomy
Gastric atrophy secondary to caustic material

Abnormal results in both stages

Ileal disorders
Bacterial overgrowth of small intestines
Pernicious anemia and other disorders listed above (some cases prior to cobalamin replacement)
Pancreatic disorders
Inadequate urinary collection
Renal failure
Fish tapeworm infestation

Treatment

The important aspect of Vitamin B12 therapy is that it should be lifelong. The arbitrary recommended dosage of daily injections of 1,000 mg of Vitamin B12 for the first week, followed by weekly injections for the first month and, then, monthly injections for the rest of the patients life is commonly used because of the negligible toxicities associated with such therapy.

Hemolytic Anemias

Autoimmune hemolytic anemia (AHIA) is the most common cause in elderly patients. The diagnosis is made by the finding of a positive Coumbis test. In the elderly patient, the anemia is more likely to be associated with a lymphoproliferative disorder (non-Hodgkins lymphoma or chronic lymphocytic leukemia), collagen vascular disease or drug ingestion.

Steroids and spleenectomy are usually effective in patients with red cell antibodies of the IgG type. Immunosuppression medication can be used in steroid resistant cases and are usually successful.

Microangiopathic hemolytic anemia is a disorder of importance in older patients. Fragmentational hemolysis may result when blood flow through small vessels is impeded by the presence of microthrombi or by intrinsic disease of the vessel wall. This is usually associated with severe infections or disseminated neoplasm and presents not only with hemolytic anemia but also a consumptive coagulopathy. The finding of red cell fragmentation thrombocytopenia, a prolonged PTT and a hemosiderinuria should suggest this diagnosis.

Myelodysplastic Syndromes (MDS)

MDSs are common in the elderly patient. They are bone marrow stem cell disorders that lead to ineffective and disorderly hematopoiesis. They manifest as irreversible quantitative and qualitative defects of hematopoietic cells caused by abnormal division, maturation and production of erythrocytes, granulocytes, monocytes and platelets. The disorder presents with macrocytosis or a dimorphic red cell morphologic pattern (a microcytic subpopulation of red cells with the remaining cells being normocytic).

The median age at which MDS is diagnosed is between 60-75 years. Signs and symptoms are nonspecific and generally relate to the blood cytopenias. Fatigue, weakness and malaise are common. A small percentage of patients have splenomegaly. Hepatomegaly is rare. The bone marrow has features suggesting a DNA synthetic disturbance or abnormality in iron distribution. The most important findings in the bone marrow are the dysplastic changes and, in some cases, increased hyeloblasts. The common chromosome abnormalities seen in MDS are trisomy, loss of the long arm of chromosome 5, 7, 8 or 9 monosomy. The etiology is unknown.

The treatment of MDS in elderly patients is different from that of young patients as they are not candidates for bone marrow transplant and do not tolerate intensive cytotoxic treatment. Options to be considered include observation, low-dose chemotherapy, recombinant erytropoietin or colony-stimulating factor that can increase circulating formed blood elements and cis-retinoic acid, which has been shown to facilitate hematopoietic cell differentiation. High dose chemotherapy should be used with caution. Effective, safe therapy for the patient with MDS has yet to be developed.

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