Overview

Anemia is an important sign that often points to a serious and possibly treatable medical condition. Although defined as a reduction in red blood cell (RBC) mass, other readily available measures that estimate RBC mass, such as hemoglobin (Hb) concentration and hematocrit (Hct), are commonly used. In elderly persons (defined as those older than age 65 y for the purpose of this article), the etiology of anemia differs sufficiently from the etiology in younger adults to warrant considering anemia in elderly persons as a distinct entity. A comprehensive history, physical examination, and laboratory evaluation are required for an elderly person found to have anemia. As a laboratory finding, anemia is often recognized incidentally after the initial evaluation. The multiple causes for anemia in elderly persons and the influence of anemia and anemia treatment on the pathogenesis of associated conditions justify a complete anemia evaluation rather then a piecemeal approach. Consult a hematologist for bone marrow aspiration and biopsy. Consult a gastroenterologist for colonoscopy, esophagogastroduodenoscopy, or small bowel evaluation. Low Hb is a powerful prognostic marker for multiple adverse outcomes in the elderly. Clinicians should be alerted to the increased risk of morbidity, hospitalization, and mortality in cases of anemia in the elderly. The critical element in treating anemia is to identify reversible etiologies for the anemia (eg, iron deficiency, infection) and treat these appropriately. Iron deficiency, vitamin B-12 deficiency, and folate deficiency should be evaluated and treated in cases of anemia in elderly persons. Aside from addressing underlying etiologies or comorbid conditions, intervention to correct anemia remains experimental. Medications in patients with anemia are used based on the cause of the anemia in an elderly person. For unexplained anemia, no treatment has been well studied. Medications include erythropoiesis-stimulating agents, oral mineral supplements (used in mineral deficiencies), and colony-stimulating factors (used to enhance erythropoiesis when endogenous erythropoietin [EPO] levels are low). Unless a deficiency has been identified as a cause of anemia in an elderly person, no specific dietary intervention will be fruitful. Activity restrictions may be considered for symptomatic anemia in elderly patients who may have active cardiac symptoms until an appropriate cardiac evaluation has been performed. Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.

Patient Education
It is invaluable for elderly patients with anemia to have documentation of their Hb concentration if it is low. Thus, if hospitalization occurs, their baseline Hb will be available. For patient education information, see Anemia.

Hematopoiesis
Hematopoiesis, the production of blood elements, occurs in an orderly, hierarchical fashion. Blood cell production requires stem cells, a functioning bone marrow microenvironment, nutrients, and cytokines. A pluripotent hematopoietic stem cell gives rise to committed progenitors of myeloid, erythroid, and megakaryocytic lineages. Erythropoiesis specifically relates to the arm of hematopoiesis that generates erythrocytes. The earliest committed erythroid lineage progenitors include the BFU-E (burst-forming uniterythroid), which later gives rise to the CFU-E (colony-forming unit-erythroid). Normal erythropoiesis in adults occurs exclusively in the bone marrow and is generally restricted to the pelvis, vertebrae, sternum, ribs, and proximal femurs.

Erythropoietin physiology
Various hematopoietic growth factors support stem cell proliferation, differentiation, and survival. EPO, a glycoprotein that is a hematopoietic growth factor, serves as a primary regulator of RBC production.[1, 2] Synthesis and EPO regulation occurs primarily in the kidney, with a smaller contribution by liver hepatocytes.[3, 4, 5, 6, 7] As a consequence, renal failure inexorably leads to anemia from impaired EPO production. Reduced tissue oxygenation (rather than diminished RBC production), typically from anemia or hypoxia, potently stimulates a logarithmic enhancement of EPO synthesis. [8] Elevated serum EPO levels enhance erythrocyte production primarily by inhibiting apoptosis of erythroid progenitor cells and to a lesser degree by enhancing erythroid progenitor proliferation and differentiation.[9] The reticulocyte, an early RBC that has lost the nucleus but retained the polyribosomal reticular network, eventually emerges into the blood. After 1-4 days, reticulocytes lose this ribosomal network and mature into RBCs. Mature RBCS have an average life span in the blood of 100-120 days. Macrophages engulf senescent RBCs in the spleen, liver, and marrow.

Estimates of RBC mass
RBCs are largely composed of Hb, which is a complex molecule that is essential to delivering oxygen from the lungs to the tissues. Hb contains a heme-iron complex, and each RBC has hundreds of millions of Hb molecules. Thus, the RBCs serve as the largest storage compartment of iron in the body, and RBC loss often leads to iron deficiency.

A wealth of data shows that important causes are uncovered if an evaluation is performed for anemia as defined by the WHO threshold. often 12 g/dL above the WHO threshold. The most common causes include iron deficiency (with or without blood loss). and chronic kidney disease. in the majority of cases of anemia in elderly persons. myelodysplastic syndromes.) Moreover. Nevertheless.[11. acute or chronic leukemia. hypersplenism. The Hb value below which anemia is defined varies. Despite a complete evaluation. thus. different thresholds are considered: • • • Prognostic marker: Numerous studies have shown that mildly low Hb values. below. The World Health Organization (WHO) Hb thresholds of less than 13 g/dL for men and less than 12 g/dL for women are the most common definitions used for anemia in the elderly. Hb thresholds for anemia may be defined distinctly for various reasons. Etiology Multiple conditions can lead to anemia in elderly persons. an etiology can be found. a significant minority of cases have no etiology uncovered (ie. the WHO criteria remain useful to compare anemia prevalence in different studies. Treatment: A lower Hb threshold is often used when deciding whether to treat with pharmacologic erythropoietin or RBC transfusions. diseases of the bone marrow (eg. 15] Table 1. chronic disease/inflammation. paroxysmal nocturnal hemoglobinuria. [10] The threshold has been widely criticized based upon an association of adverse outcomes with higher Hb concentrations. 16] Other etiologies of anemia in the elderly include deficiencies of folate or vitamin B-12.[14. aplastic anemia. (See Table 1. Etiologic marker: Clinicians most often define anemia to determine if an etiologic evaluation should be pursued. have been associated with increased mortality. lymphoma). myeloproliferative syndromes. 15. 12] However. the anemia may be multifactorial.[13. and functional decline in elderly persons. unexplained anemia). Prevalence of Various Etiologies of Anemia in Elderly Persons (Open Table in a new window) Cause Iron deficiency Chronic disease/inflammation Chronic kidney disease Endocrinopathies Vitamin B-12 or folate deficiency Myelodysplastic syndromes Unexplained Prevalence 15-23% 15-35% 8% Less than 5% 0-14% 0-5% 17-45% . 14. and hemolytic anemia.Anemia Thresholds In the vast majority of patients. hypothyroidism. hospitalization. Hb represents an excellent and easily reproducible measure of RBC mass.

especially considering that renal function declines with aging. with or without low to normal transferrin. has been used. a protein that transports iron out of cells that store it. In epidemiologic studies. increases hepcidin expression.[13] An alternative method is to consider anemia of chronic inflammation to exist when the patient has an inflammatory comorbid condition. or even conditions leading to anemia. warrant a diagnosis of anemia of chronic inflammation. No established diagnostic criteria for anemia of chronic inflammation exist.[15] Not all conditions.[19] Anemia of chronic inflammation is a hypoproliferative anemia characterized by low serum iron and adequate to increased iron stores. may respond to hormonal therapy.[32] Renal insufficiency Chronic kidney disease is an important cause of anemia in elderly persons. whereas hypertension may cause anemia from chronic kidney disease. particularly in elderly persons. Inflammation.Iron deficiency anemia Identifying iron deficiency anemia in elderly persons is essential. Hepcidin is a hepatically synthesized. < 60 μg/dL). including malignancy. [17. Hepcidin directly inhibits ferroportin. 22] interleukin-1 (IL-1).[20] Thus.[28] The discovery of hepcidin has considerably clarified the pathophysiology of anemia of chronic inflammation. iron deficiency. particularly with IL-6. iron deficiency anemia represents only 15-23% of cases of anemia among the elderly. known as primary defective iron-reutilization syndrome.[29. Anemia of chronic inflammation and the disordered iron homeostasis that is typically found may be explained by increased hepcidin expression. 27] Inflammation inhibits erythropoiesis through a variety of mechanisms. Case reports have proposed that anemia of chronic inflammation may exist in elderly persons absent a chronic condition.[21. anemia due to renal insufficiency or endocrine dysfunction is not considered anemia of chronic inflammation. low serum iron (eg. For example.[23. thus leading to the term anemia of chronic inflammation. and the condition can be corrected. Comorbid diseases often contribute indirectly to anemia of chronic inflammation. 34] Reduced renal EPO production is the . More importantly.[13.[26. 14. 30] Hepcidin testing is not clinically available and has not been validated as a diagnostic test for anemia of chronic inflammation.[31] This entity. 18] Despite the importance of establishing a diagnosis. 15] Anemia of chronic disease and inflammation Anemia of chronic disease appears to be primarily related to inflammation. diseases such as hypertension and osteoarthritis should not lead directly to anemia.[33. often points to an underlying gastrointestinal pathology. 24] interferon gamma (IFNgamma).[20] Inflammatory markers implicated in anemia of chronic inflammation include tumor necrosis factor alpha (TNF-alpha).[25] and IL-6. 25-amino acid peptide that serves as a primary regulator of iron homeostasis. Nonsteroidal drugs for osteoarthritis may lead to gastrointestinal bleeding and iron deficiency.

and renal insufficiency. 36] The precise degree of renal dysfunction sufficient to cause anemia remains controversial. or even normal white blood cell (WBC) count. Elderly patients with acute leukemia can have a more smoldering disease course than younger patients. pernicious anemia or hemolysis. Often (but not always). although in most individuals the WBC differential is abnormal. . Chronic lymphocytic leukemia (CLL) is common in elderly persons. including thrombocytopenia. 38] A study among community-dwelling elderly persons suggested anemia and low EPO levels are independent of age and other factors at a creatinine clearance of less than 30 mL/min. should be considered in every patient with anemia.primary factor leading to anemia in chronic kidney disease.[40] and 43% had chronic kidney disease (defined as a creatinine clearance of less than 60 mL/min). This fact emphasizes the importance of performing a manual differential in all patients with an abnormal complete blood count (CBC). They are more common in older adults and may present as an isolated anemia. Chronic kidney disease increased the risk of anemia. as this a medical emergency requiring prompt intervention. respectively). 47] When evaluating mean corpuscular volume (MCV). 46. Myelodysplastic syndromes Myelodysplastic syndromes represent a heterogeneous group of disorders characterized by clonal hematopoiesis and peripheral blood cytopenias.[39] Renal function in older residents in a skilled nursing facility was also examined. Although most patients will have either an elevated WBC count or lymphadenopathy at presentation. thrombocytopenia. 44] Alternatively. in part related to widespread vitamin supplementation. Thrombotic thrombocytopenic purpura (TTP). Mild Hb decreases in adults may be detected at a creatinine clearance of 40-60 mL/min.[45. vitamin B-12 deficiency is a very uncommon cause of anemia in elderly persons. Thus. However. Serum EPO levels have been shown to be inappropriately low at a creatinine clearance of less than 40 mL/min.[43.[41] Folate deficiency is also uncommon. they remain important to identify. [35. one must be cognizant that recent RBC transfusions will alter the values. myelodysplastic syndrome is an unlikely cause of idiopathic normocytic anemia in elderly persons. Other primary hematologic disorders A variety of other primary hematologic disorders have anemia as a manifestation. altered mental status. patients will have other cardinal features of the disease. anemia in conjunction with macrocytosis. In the elderly.[37. although rare. some patients will present with autoimmune hemolytic anemia and could have relatively little evidence of CLL. or neutropenia absent another cause raises the suspicion of myelodysplastic syndrome. Nutrient deficiencies Low vitamin B-12 levels in elderly persons are not uncommon. These patients may present with a low.[42] To the extent that such mineral deficiencies are reversible and suggest other conditions (eg. high. retrieving hematology values before a transfusion is critical.

the more severe the thyroid dysfunction. Patients with aplastic anemia will have a low WBC and/or platelet count.[52] However. Multiple studies of anemia in elderly persons over the past 30 years have confirmed that unexplained anemia represents a considerable proportion of cases of anemia in elderly persons.[13] C-reactive protein (CRP) was elevated in 27% of patients who had anemia of chronic inflammation. Thyroid disease Hypothyroidism reduces RBC mass and may lead to a normocytic anemia. Hb slowly. 54. 53. 55] Even with the advent of better tests. Guralnik and colleagues evaluated data from community-dwelling elderly and defined anemia of chronic inflammation as a serum iron less than 60 μg/dL but without iron deficiency. hypothyroidism may lead to macrocytosis without anemia. [48] Occasionally. usually older.[49] Hypothyroidism and hyperthyroidism may be associated with pernicious anemia. compared with only 9% in those with unexplained anemia. such as serum ferritin. measurement of a lactate dehydrogenase (LDH) level is essential. the more likely anemia will occur. Patients with myeloproliferative diseases often have an elevated WBC count. a significant portion of elderly persons with anemia will be diagnosed as having unexplained anemia. anemia can be a sign of bone marrow infiltration from lymphoma. but most patients with thyroid abnormalities are not anemic.9 mg/dL for those with anemia of .[15] Whether unexplained anemia represents a spectrum of undiagnosed etiologies or has a unifying pathogenesis remains unclear. but predictably.[15] Unexplained anemia is generally a condition of elderly persons. and soluble transferrin receptor. In these patients. A therapeutic trial correcting the thyroid abnormalities may be necessary to definitively determine their role in causing lower Hb concentration. [50.[56] In a longitudinal study in healthy elderly subjects. The present data support unexplained anemia as distinct from anemia of chronic inflammation. it has long been recognized that a proportion of patients.[8] In elderly patients who reside in nursing homes. the mean CRP was 36. Not uncommonly. It appears more commonly with advancing age and is rarely. a very high prevalence of unexplained anemia has been found (45%). Generally. 16. the patient will not have palpable lymphadenopathy. Unexplained anemia in elderly persons The traditional notion has been that anemia in elderly persons always reflects a serious underlying condition. 13. ranging from approximately 15-45%. some patients with myelofibrosis will have anemia as the prominent abnormality. have anemia that does not meet diagnostic criteria for a specific etiology (unexplained anemia). however.Multiple myeloma should always be considered. Finally. encountered in younger adults. 51] The degree of thyroid dysfunction leading to anemia remains unknown. but computed tomography (CT) scans could reveal extensive internal lymphadenopathy. In a nursing-home study categorizing anemia of chronic inflammation as the presence of an inflammatory comorbid condition. declined with aging. 15. [50] and both conditions may also lead to a correctable anemia. if ever. methylmalonic acid. 14.[5. particularly in patients with elevated globulin levels.

chronic inflammation.0 mg/dL for patients with unexplained anemia. anemia of chronic inflammation as diagnosed by criteria that differed in 2 studies showed higher markers of inflammation for anemia of chronic inflammation relative to unexplained anemia.5 g/dL on average. the presence of significant inflammation (ie. 39] Sex hormones The general Hb difference between men and women relates in large part to the erythropoietic effects of testosterone.[58] A similar blunted EPO response occurs in patients with diabetes independent of reduced glomerular filtration. high CRP) should alert the clinician to a possible inflammatory component. which can be illustrated by the fact that after orchiectomy or androgen deprivation therapy for prostate cancer. however.[62] Thus.3 pg/mL +/– 72. 15. compared with cases of unexplained anemia (8.[8] A decline in renal function may be a feature of aging that is accentuated by hypertension and diabetes. potentially from early renal damage. Thus. Hb falls by 1.[8. have a blunted endogenous EPO response to anemia. [13. For example.8). 61] In older adults with preserved renal function.5 pg/mL +/– 7. a leukocyte count less than 3 K/uL. Another concern has been that unexplained anemia reflects occult myelodysplastic syndrome.[59] Finally.[8. diabetes and hypertension) is blunted relative to those not having such a condition.[15] Relative EPO deficiency In the prototypical model of complete renal failure. 17% of cases of unexplained anemia had hematologic abnormalities that may have been consistent with myelodysplastic syndrome. children with nephritic syndrome. 3 of 30 patients. [60. likely contributes to unexplained anemia. endocrine function as measured by the endogenous EPO response to anemia may be impaired.[63. In a nursing home study. compared with 6. when patients are undergoing treatment for a chronic inflammatory disease.[36] Even in renal conditions without overt renal glomerular filtration abnormalities. The expected inflammatory profile may be blunted. or 10%. the endogenous EPO response in those having renal-damaging conditions (ie.[67] .2 g/dL to 1. Although higher inflammatory markers have not been used as the sole criterion for the diagnosis of anemia of chronic inflammation. or a platelet count less than 150 K/uL. inadequate endogenous EPO secretion rather than a primary marrow problem leads to anemia. with unexplained anemia).4). testosterone replacement raises Hb in older men.[13] These included an MCV greater than 100 fL. IL-6 levels were significantly higher in cases of anemia of chronic inflammation (44. 64] Testosterone declines with aging in men. 27 patients exhibited a normocytic unexplained anemia.[65] The greater rate of Hb decline in men than in women with advancing age raises the suspicion that falling testosterone may cause unexplained anemia. before significant renal clearance impairment. administration of angiotensinconverting enzyme (ACE) medication may suppress EPO secretion and precipitate anemia. 57] In the National Health and Nutrition Examination Survey III (NHANES III) study of anemia in the elderly. 66] Further. whereas 3 patients had an unexplained macrocytic anemia (ie. a relative EPO deficiency.

One estimate suggests that more than 3 million elderly Americans are anemic.) Table 2.5 g/dL) 48% Studies from Europe and Japan indicate a fairly similar prevalence of anemia in elderly adults in those parts of the world as in the United States. ≥65 y Hospitalized 1992[14] Artz et al. Prognosis Morbidity and mortality related to anemia in the elderly can occur from the underlying disease related to the anemia and from the adverse effects of anemia itself. 73. one small study did not show a difference in testosterone between anemic and nonanemic older men. However.[13] Prevalence In addition to the varying thresholds for anemia. with a 5-year annual follow-up. 75] Increased difficulty with mobility[73. 10. ≥65 y Community-dwelling [68] 2007 Italian Denny et al. below. ≥71 y Community-dwelling 2007[69] Joosten et al. Anemia Prevalence in the Elderly Based on WHO Criteria (Open Table in a new window) Study Age Population Guralnik et al. including the following: • • • • • • Increased mortality[12. 71. 76] Falls[77. < 14 g/dL) and a worse outcome. 74] Increased hospitalization[12. 70. 11% 24% 24% (defined as Hb < 11.[45] and the proportion of unexplained anemia appeared similar in men and women.A large epidemiologic study showed that men with lower testosterone were more likely to have anemia. 78] Decreased activities of daily living and instrumental activities of daily living[69] The presence of other conditions (cardiovascular disease) appears to increase the negative prognostic impact on survival In a Dutch study of 562 elderly persons aged 85 years. den Elzen et al found that the 26. 72.6% elderly. Prevalence estimates of anemia in elderly persons living in developing countries are lacking. the highly heterogeneous nature of the elderly population has lead to multiple estimates of anemia prevalence in the elderly. Multiple epidemiologic studies show an association between anemia or even mildly low Hb above the WHO threshold for anemia (ie. 2004[15] Most ≥65 Nursing home y Prevalence elderly. 69. 72. ≥65 y Community-dwelling 2004[13] American Ferrucci et al.7% of study participants who had anemia at baseline had more .[13] (See Table 2.

The cause for the higher prevalence of anemia in blacks has not been established. prevalent and incident anemia were associated with an increased risk of death. one study showed anemia prevalence was 8% among those aged 65-74 years. incident anemia during follow-up was associated with an additional increase in disability in basic activities of daily living.[8] This change is more pronounced in men.[13] The reason for increased anemia prevalence with advancing age has not been established. [19. bleeding.disability in instrumental activities of daily living than did the other participants. 13% for those aged 75-84 years. Epidemiology Race Anemia is approximately 3 times more prevalent in elderly blacks than it is in non-Hispanic whites.[79] Moreover.[19. Transfusion history . Age Hb declines slightly and anemia prevalence rises in men and women with advancing age. Some of the difference stems from employing a lower Hb threshold (eg. The causes for an acute fall in Hb are narrow (eg. Among community-dwelling adults aged 65 years and older. Hb < 12 g/dL) for women than for men (ie. History and Physical Examination Previous blood counts Previous blood counts represent one of the most underused and invaluable tools to help clinicians determine the acuity of the anemia. some of the disparity is likely related to biologic differences. and 23% for those aged 85 years and older. However.8 g/dL lower than for whites. Anemia is more common in black children. 26] Sex Anemia in elderly persons is more common in men than in women. < 13 g/dL). with the median Hb for elderly blacks being approximately 0. hemolysis). part of the increased anemia prevalence relates to an alphathalassemia trait.[33] and Hb appears to decline similarly with advancing age in blacks and whites.[34] Whether anemia has different adverse consequences in blacks is unclear.[19] In younger adults. 26] Older Mexican Americans have a fairly similar prevalence of anemia to that of elderly whites. as opposed to the more common slow decline over time.[79] Also. Elderly persons have frequently had previous blood counts that are easily retrievable.

Racial background Family history can be useful for considering a coexistent thalassemia trait or other hemoglobinopathy. including myelodysplasia. shortness of breath. presence or symptoms of cancer. the prehospitalization Hb can be invaluable. with a recognition that blacks may have approximately 0. especially myelosuppressive chemotherapy). chronic kidney disease. the patient has often had a preexisting low Hb before the surgery. or both. cancer (and cancer chemotherapy. The anemia is often the consequence of multiple phlebotomies. gastrointestinal blood loss. The nonspecific nature of anemia-related symptoms poses a major challenge. the depth of the Hb fall. Special attention should be paid to elements that indicate a cause for the anemia (eg. Conditions that are associated with specific types of anemia should be clearly identified.8 g/dL less Hb than whites. Nevertheless. to gather additional objective information is often useful. as well as the acute illness itself. Diseases that frequently cause anemia should be noted. unless an erythropoietinstimulating agent is administered. . When surgery requires RBC transfusion. tinnitus). Inquiring about specific tasks. arthritis) and symptoms related to anemia (fatigue. a detailed history often identifies the presence of anemia-related symptoms.One should inquire whether RBC transfusions have previously been administered. as well as marrow hypoproliferation and gastrointestinal bleeding. A history of transfusions will alert the clinician to a chronic problem. had another condition preventing an appropriate response to blood loss. particularly in elderly persons. and rheumatologic disorders. Alcohol overuse may go unrecognized in the elderly and leads to deficiencies of vitamin B-12 and folate. infection. Lymphoproliferative and autoimmune disease may cause autoimmune hemolytic anemia. Ancestry should be considered. Previous chemotherapy or radiotherapy raises the possibility of therapy-related myelodysplastic syndrome. End-stage renal disease (ESRD) uniformly causes anemia. Thus. Patients may mistakenly attribute decreased energy to aging or other medications. such as walking up stairs. Symptoms Symptoms relate to the rapidity of the anemia. Medical history Recent hospitalization often results in anemia. Recent surgery suggests blood loss and necessitates comparison to preoperative Hb values. and concomitant medical conditions.

Blood loss should be directly inquired about (eg. or both. however. Thus. hematemesis). Special attention should be paid to the following: • • • • • • • • • Pallor Icterus Lymphadenopathy Tachycardia Cardiac murmurs Hepatomegaly Splenomegaly Edema Stool for color . red blood in the stools. such as ice or dirt) Koilonychia (spoon-shaped changes in the nail beds) Dysphagia (from esophageal webs) Mouth and tongue soreness (from atrophy) Signs and symptoms of vitamin B-12 deficiency may include the following: • • • Neuropathy Ataxia Dementia Signs and symptoms of hemolysis may include the following: • • Jaundice Dark urine (if intravascular hemolysis) Physical examination The physical examination may uncover an anemia etiology. signs related to the anemia. hemoptysis.Most symptoms of anemia are nonspecific. General symptoms include the following: • • • • • • • • • Fatigue Weakness Dyspnea on exertion Tinnitus Presyncope Palpitations Headache Poor concentration Pale skin Signs and symptoms of iron deficiency may include the following: • • • • • Blood loss (tarry stools. melena. a temporal relation between falling Hb and symptom exacerbation is very useful. the examination must be comprehensive. hematuria) Pica (desire to consume unusual substances. hematuria.

Several common facts guide the evaluation. Such an investigation must account for the unique epidemiology in this population. malignancy. the more likely an obvious and/or serious cause will be detected . or rheumatologic disease Anemia of chronic renal insufficiency Aplastic anemia Blood loss Chronic lymphocytic leukemia Chronic myelogenous leukemia Folic acid deficiency Hairy cell leukemia Hemolytic anemia Hyperthyroidism Hypothyroidism Iron deficiency anemia Lymphoma Medications Multiple myeloma Myelodysplastic syndromes Myeloproliferative syndromes Neoplasia (nonhematologic) Paroxysmal nocturnal hemoglobinuria Pernicious anemia Splenomegaly Thalassemia trait Thrombotic thrombocytopenic purpura Unexplained anemia of the elderly Vitamin B-12 deficiency Laboratory Evaluation Numerous algorithms have been proposed for the evaluation of anemia and anemia in elderly persons. or peripheral smear.• Stool test for blood Differential Diagnosis Problems to be considered in the differential diagnosis of anemia in the elderly include the following: • • • • • • • • • • • • • • • • • • • • • • • • • • • Acute lymphoblastic leukemia Acute myelogenous leukemia Anemia of chronic inflammation/anemia of chronic disease from infection. RBC size (using the MCV). the more severe the anemia. reticulocytosis is inadequately low) Generally. They are often based on kinetic measures made by first assessing the reticulocyte count. as follows: • • Most anemia in elderly persons is hypoproliferative (ie.

• • • • Previous blood counts are often available Approximately one third of older subjects will have an unexplained anemia. major surgery) Hb that does not recover to baseline after an acute event Falling Hb and symptoms that may be related to anemia Should the anemia etiology not be apparent from the initial history and physical examination. or both. the blood counts should be reevaluated after identifying the problem. this initial evaluation will lead to a presumed etiology for the anemia. Once a deficiency is identified. correcting the deficiency. Recommended studies include the following: • • • • • • • • • • • • CBC count (with WBC differential. Other tests often performed include the following: • • • • CRP Serum EPO Hepatic transaminases Urine immunoelectrophoresis Possible hemolysis may be evaluated with the following: • • • Indirect bilirubin and direct bilirubin Serum haptoglobin Direct and indirect Coombs tests . where no proximate cause can be identified A peripheral smear is often unavailable for direct examination or is difficult to interpret Anemia can be multifactorial Initiate an evaluation under the following conditions: • • • • Hb below the WHO threshold (Hb < 13 g/dL for men. A reiterative process is essential. a comprehensive evaluation is useful. and RBC parameters [MCV]) Examination of peripheral blood smear Reticulocyte count LDH Serum ferritin Serum iron Total iron-binding capacity Vitamin B-12 Folate Thyroid-stimulating hormone Serum creatinine and estimated glomerular filtration rate Serum protein electrophoresis. < 12 g/dL for women) Hb that has fallen more than 2 g/dL over any period without an adequate explanation (eg. platelet count. especially if total globulins are elevated In about two thirds of elderly persons with anemia.

alcohol use or liver disease leads to increased RBC size. For example. Although microcytosis occurs in iron deficiency anemia.[81] Intermediate ferritin values between 18 and 44 ng/mL are highly suggestive of iron deficiency in the elderly. every elderly anemic adult requires a thorough evaluation to determine the underlying cause of iron deficiency. can also be used in the evaluation of hemolysis. ferritin can be elevated in inflammation. rather than a technician-reported analysis of the peripheral smear. including RBC MCV. serum iron. This generally requires a hematology or pathology review. leading to an Hb value of less than 10 g/dL. nor does a normocytic anemia exclude iron deficiency. the more likely a specific cause will be identified. That said. iron saturation. Further. and bone marrow examination. especially when determining if a primary bone marrow process accounts for macrocytic anemia. The more severe the anemia and the more severe the macrocytosis. microcytosis is a late finding and typically occurs only after chronic iron deficiency. raising the threshold for serum ferritin in the elderly to account for increased inflammation related to aging and/or comorbid conditions enables reasonable sensitivity and specificity for iron deficiency anemia. . an initial MCV of 85 and an Hb of 12 g/dL changes to an MCV of 75 and an Hb of 9. If no cause is identified. soluble transferrin receptor (sTFR).• • Urine Hb Urine hemosiderin (Splenic ultrasonography. Serum ferritin is the most useful test for diagnosing iron deficiency anemia. Evaluation of Iron Deficiency Serum iron is not an adequate test to exclude iron deficiency. Peripheral blood smear A peripheral blood smear is invaluable. [83] Thus.[80] As an acute phase reactant. a developing microcytic anemia in an older adult. The impact of other factors may abrogate the standard changes in cell size. including malignancy. reticulocyte Hb content. an imaging test. complicating the diagnosis of iron deficiency anemia in the presence of inflammation. erythrocyte protoporphyrin. < 12 ng/mL) is highly specific for iron deficiency anemia. Because iron deficiency is correctable and often reflects gastrointestinal pathology. absent an obvious chronic inflammatory disease. serum transferrin.) Androgen insufficiency may be evaluated with a testosterone level. [82. Numerous tests are available to diagnose iron deficiency. Iron deficiency occurs in approximately 20% of elderly anemic patients.5 g/dL). 83] and ferritin values above 100 ng/dL make iron deficiency highly unlikely. Low serum ferritin (eg. a hematology referral and/or bone marrow examination should be considered. serum ferritin. is highly suspicious for iron deficiency (eg. A major pitfall is misinterpreting the MCV. the MCV is an average of all the RBCs analyzed.

85] Further. most commonly employing the sTFR. gastrointestinal bleeding causes anemia through iron deficiency. sTFR is less sensitive in detecting early iron deficiency compared with ferritin. Once must be careful not to judge the patient’s wishes. when iron availability for erythropoiesis is low. in addition to cost and inconvenience. if ever. Other tests for iron deficiency include the following: • • • • • • • Fecal occult blood test Urine analysis for blood Colonoscopy Esophagogastroduodenoscopy Small bowel study Urine hemosiderin Anti-tissue transglutaminase antibodies Many older adults are subject to unnecessary endoscopic procedures for anemia. Low vitamin B-12 levels are frequent in older adults. Alternatively. if iron stores are adequate and the anemia persists. Bone marrow evaluation has been considered the criterion standard for iron deficiency. but they are essential to exclude as causes of anemia. raising the threshold of ferritin to less than 30-50 ng/mL affords a similar or better diagnostic performance. malabsorption) should be investigated and vitamin B-12 replenished. However. as these conditions are treatable and usually highlight the presence of another condition. then etiologies of vitamin B-12 deficiency (eg. a ratio greater than 2. If a level of less than 200 pg/mL is detected. By using the log of the sTFR/ferritin. pernicious anemia. Unless acute bleeding is occurring. Occasionally the patient is too ill or the family does not desire an evaluation. An elevated . For equivocal levels of vitamin B-12. STFR enhances diagnostic sensitivity in elderly persons compared with using a very low serum ferritin for iron deficiency anemia. bone marrow examinations can be highly misleading and may require up to 7-9 aspirate smears to confidently prove iron stores are absent. identify the cause of the anemia in elderly persons. Folate deficiency has become very uncommon with routine supplementation.[83. The sTFR is a truncated fragment of the membrane receptor that is increased in iron deficiency. a thorough endoscopic evaluation is often necessary rather than only prescribing iron replacement. should iron deficiency be suspected.Alternative strategies to diagnose iron deficiency anemia have been studied. evaluate methylmalonic acid. pernicious anemia should be considered in patients with vitamin B-12 deficiency. and clinicians should approach the patient and family with the options.[84] Another method standardizes sTFR based on the serum ferritin. 88] Thus. such as a level between 200 and 350 pg/mL. an endoscopic evaluation will rarely. However. serum ferritin remains the standard test to exclude iron deficiency in the elderly.[87. Thus. For example. Evaluation of Vitamin B-12 and Folate Deficiencies Vitamin B-12 and folate deficiencies are uncommon.5 may indicate iron deficiency.[86] The lack of laboratory standardization in reporting or a standardized value that is diagnostic of iron deficiency further complicates the use of sTFR.

Normal laboratory ranges for MCV vary. normocytic. Potential causes for macrocytic anemia include the following: • • • • Vitamin B-12 deficiency Folate deficiency Medications (myelosuppressive anticonvulsants) Alcohol overuse chemotherapy. occult inflammation. inappropriately low serum EPO level. This anemia is generally mild (Hb from 9-12 g/dL. An MCV greater than 95-100 fL defines macrocytosis. as this more often reflects other conditions or bone marrow pathology. The authors use an MCV of 100 fL or greater or an MCV of 95 or greater but rising more than 5 fL from previous counts. One must recognize that methylmalonic acid is elevated in renal dysfunction. Macrocytosis. neutropenia. evaluate for vitamin B-12 deficiency and empirically treat the patient. However. Evaluation of Macrocytic Anemia Macrocytic anemia in older adults truly demands a thoughtful investigation of potential causes. and myelodysplastic syndromes. thrombocytopenia. Evaluation of Unexplained Anemia Increasingly. Commonly. . or weight loss should prompt consideration of a bone marrow examination. because serum EPO should rise with declining Hb values. The EPO level usually falls within the normal reference range. The diagnosis of unexplained anemia assumes the clinician has excluded serious causes. it has become recognized that approximately one third of older adults do not have an obviously discernible cause of anemia upon an extensive evaluation. the authors advocate considering a bone marrow examination in all patients who required RBC transfusion who otherwise have an unexplained anemia. splenomegaly. early satiety. Homocysteine is elevated in vitamin B-12 deficiency and folate deficiency. chills. and hypoproliferative [low reticulocyte count]). Potential explanations for the anemia have included low testosterone. Reevaluating the anemia after treatment is essential. or unexplained constitutional symptoms of fever.methylmalonic acid level is evidence of a vitamin B-12 tissue deficiency. which indicates that the low nutrient level was not causative. reduced hematopoietic reserve with advancing age. However. The threshold to pursue a bone marrow examination to exclude myelodysplastic syndromes remains unknown. trimethoprim. this finding is abnormal. the presence of an MCV greater than 115 fL is highly suspicious for the megaloblastoid anemia that is seen with these deficiencies. hydroxyurea. Anemia due to vitamin B-12 or folate deficiency need not be macrocytic. However. If the methylmalonic acid is elevated in the setting of anemia and a low vitamin B-12. bone pain. It is clear that this anemia is typically associated with a low serum EPO level for the degree of anemia. the anemia does not correct.

Epogen) and darbepoetin-alfa (Aranesp). volume overload. . particularly older adults not on dialysis and not receiving RBC transfusions. remain unexplored. potentially. In light of the increased risk of thrombosis. Recommendations for Hb thresholds below which RBC transfusions should be given vary from 5-10 g/dL. aplastic anemia) is suspected. Gaucher disease). and costs. Bone marrow examination generally has fewer complications and is less invasive than generally appreciated. the marrow is used to accurately gauge iron stores. and often underappreciated. MDS should be diagnosed based on a bone marrow examination and not only on the peripheral smear. and.[89] the risks and benefits associated with the treatment in patients with chronic kidney disease. Erythropoiesis-Stimulating Agents Erythropoiesis-stimulating agents (ESAs) approved in the United States include epoetin-alfa (Procrit. Occasionally. Transfusions entail numerous. hypertension. Repeated transfusions can result in iron overload and clinical manifestations of hemochromatosis. as patients will be more symptomatic from a more acute drop in Hb. risks of infection. An ultrasonogram of the left upper quadrant can be helpful if the patient's body habitus makes examination for splenomegaly difficult. the authors generally restrict RBC transfusion to Hb levels that are less than 7-8 g/dL and are likely to continue to decline or to severe anemia symptoms. Although ESA therapy has found widespread use in the treatment of anemia due to chronic kidney disease (based on a 2006 Kidney Disease Outcomes Quality Initiative [KDOQI] consensus statement). hyperglycemia or cold agglutinin disease) Marrow disease. The primary indications are for anemia due to chronic kidney disease or cancer chemotherapy. lymphoma). RBC Transfusion For severe anemia. The need for transfusion is also related to the rapidity of the Hb drop. especially myelodysplastic syndromes Cold agglutinin disease Other Tests A bone marrow aspirate and biopsy are used when a primary marrow disease (eg. or consider nonmalignant marrow processes (eg. Because of concerns about increased mortality when using a liberal transfusion policy. infection.• • • • • • • Liver disease Hypothyroidism Chronic obstructive pulmonary disease Reticulocytosis Spurious (eg. MDS. progression of certain cancers associated with ESA use in a population at increased danger for such events. entertain marrow involvement of nonmarrow diseases (eg. transfusion reactions. RBC transfusion is warranted. Transfusing 2 units of RBCs may represent a considerable volume for elderly patients who have preexisting cardiac dysfunction. hemophagocytic syndrome.

. The authors generally use an ESA for anemia due to chronic kidney disease to obviate RBC transfusions. if the patient can be monitored closely for complications.[90. The authors will consider ESA therapy for anemia of chronic kidney disease if the Hb is less than 10 g/dL. The authors are careful not to exceed an Hb of 12 g/dL in light of the risk of increased complications at higher Hb concentrations. and if a clear quality-of-life improvement can be measured. 91] Iron supplementation is frequently needed to prevent iron-restricted erythropoiesis once an elderly patient is on ESA treatment. Prescribing of ESAs should be restricted to physicians experienced in the use and monitoring of such treatment. assuming all other etiologies have been excluded.caution must be exercised. if the patient or caregiver understands the risks.

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