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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.
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, 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.
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.  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. 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.
Treatment: A lower Hb threshold is often used when deciding whether to treat with pharmacologic erythropoietin or RBC transfusions. Etiologic marker: Clinicians most often define anemia to determine if an etiologic evaluation should be pursued. in the majority of cases of anemia in elderly persons. The most common causes include iron deficiency (with or without blood loss). myelodysplastic syndromes. and chronic kidney disease.[14. a significant minority of cases have no etiology uncovered (ie. 12] However. A wealth of data shows that important causes are uncovered if an evaluation is performed for anemia as defined by the WHO threshold. hypersplenism. often 12 g/dL above the WHO threshold. Hb represents an excellent and easily reproducible measure of RBC mass. aplastic anemia. and hemolytic anemia. acute or chronic leukemia. have been associated with increased mortality. the WHO criteria remain useful to compare anemia prevalence in different studies. below. the anemia may be multifactorial. Hb thresholds for anemia may be defined distinctly for various reasons. The Hb value below which anemia is defined varies. 14.  The threshold has been widely criticized based upon an association of adverse outcomes with higher Hb concentrations. 15. Despite a complete evaluation. chronic disease/inflammation. Nevertheless.[11. 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% . unexplained anemia). and functional decline in elderly persons.Anemia Thresholds In the vast majority of patients. thus.) Moreover. 16] Other etiologies of anemia in the elderly include deficiencies of folate or vitamin B-12. 15] Table 1. hypothyroidism. an etiology can be found. myeloproliferative syndromes. paroxysmal nocturnal hemoglobinuria. 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. Etiology Multiple conditions can lead to anemia in elderly persons. diseases of the bone marrow (eg. hospitalization. different thresholds are considered: • • • Prognostic marker: Numerous studies have shown that mildly low Hb values. lymphoma).[13. (See Table 1.
Nonsteroidal drugs for osteoarthritis may lead to gastrointestinal bleeding and iron deficiency. Anemia of chronic inflammation is a hypoproliferative anemia characterized by low serum iron and adequate to increased iron stores. often points to an underlying gastrointestinal pathology. No established diagnostic criteria for anemia of chronic inflammation exist. may respond to hormonal therapy.[29. anemia due to renal insufficiency or endocrine dysfunction is not considered anemia of chronic inflammation. < 60 μg/dL). Hepcidin is a hepatically synthesized. [17. iron deficiency. Not all conditions. More importantly. 30] Hepcidin testing is not clinically available and has not been validated as a diagnostic test for anemia of chronic inflammation. and IL-6. warrant a diagnosis of anemia of chronic inflammation.[33. 24] interferon gamma (IFNgamma). Anemia of chronic inflammation and the disordered iron homeostasis that is typically found may be explained by increased hepcidin expression.[21.Iron deficiency anemia Identifying iron deficiency anemia in elderly persons is essential. known as primary defective iron-reutilization syndrome. 14. has been used. 27] Inflammation inhibits erythropoiesis through a variety of mechanisms. 25-amino acid peptide that serves as a primary regulator of iron homeostasis. 34] Reduced renal EPO production is the . In epidemiologic studies.[26. increases hepcidin expression. or even conditions leading to anemia.[23. The discovery of hepcidin has considerably clarified the pathophysiology of anemia of chronic inflammation. whereas hypertension may cause anemia from chronic kidney disease. This entity. including malignancy. particularly in elderly persons. thus leading to the term anemia of chronic inflammation. particularly with IL-6. with or without low to normal transferrin. and the condition can be corrected. diseases such as hypertension and osteoarthritis should not lead directly to anemia.[13. An alternative method is to consider anemia of chronic inflammation to exist when the patient has an inflammatory comorbid condition. Comorbid diseases often contribute indirectly to anemia of chronic inflammation. Thus. 22] interleukin-1 (IL-1). low serum iron (eg. Renal insufficiency Chronic kidney disease is an important cause of anemia in elderly persons. especially considering that renal function declines with aging. 15] Anemia of chronic disease and inflammation Anemia of chronic disease appears to be primarily related to inflammation. a protein that transports iron out of cells that store it. 18] Despite the importance of establishing a diagnosis. Case reports have proposed that anemia of chronic inflammation may exist in elderly persons absent a chronic condition. iron deficiency anemia represents only 15-23% of cases of anemia among the elderly. For example. Inflammatory markers implicated in anemia of chronic inflammation include tumor necrosis factor alpha (TNF-alpha). Inflammation. Hepcidin directly inhibits ferroportin.
[35. Although most patients will have either an elevated WBC count or lymphadenopathy at presentation. respectively). Chronic lymphocytic leukemia (CLL) is common in elderly persons. Mild Hb decreases in adults may be detected at a creatinine clearance of 40-60 mL/min. one must be cognizant that recent RBC transfusions will alter the values. 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. they remain important to identify. This fact emphasizes the importance of performing a manual differential in all patients with an abnormal complete blood count (CBC). anemia in conjunction with macrocytosis. 47] When evaluating mean corpuscular volume (MCV). altered mental status. In the elderly. Thrombotic thrombocytopenic purpura (TTP). 36] The precise degree of renal dysfunction sufficient to cause anemia remains controversial. in part related to widespread vitamin supplementation. Nutrient deficiencies Low vitamin B-12 levels in elderly persons are not uncommon. high. although rare. patients will have other cardinal features of the disease. and 43% had chronic kidney disease (defined as a creatinine clearance of less than 60 mL/min). Other primary hematologic disorders A variety of other primary hematologic disorders have anemia as a manifestation. or even normal white blood cell (WBC) count. as this a medical emergency requiring prompt intervention. These patients may present with a low. vitamin B-12 deficiency is a very uncommon cause of anemia in elderly persons. myelodysplastic syndrome is an unlikely cause of idiopathic normocytic anemia in elderly persons. including thrombocytopenia. 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. Myelodysplastic syndromes Myelodysplastic syndromes represent a heterogeneous group of disorders characterized by clonal hematopoiesis and peripheral blood cytopenias. However. Often (but not always). To the extent that such mineral deficiencies are reversible and suggest other conditions (eg. 44] Alternatively. and renal insufficiency.[45. Serum EPO levels have been shown to be inappropriately low at a creatinine clearance of less than 40 mL/min. Renal function in older residents in a skilled nursing facility was also examined. Thus. They are more common in older adults and may present as an isolated anemia. Folate deficiency is also uncommon.[43. Chronic kidney disease increased the risk of anemia. . should be considered in every patient with anemia.[37. thrombocytopenia.primary factor leading to anemia in chronic kidney disease. retrieving hematology values before a transfusion is critical. Elderly patients with acute leukemia can have a more smoldering disease course than younger patients. although in most individuals the WBC differential is abnormal. 46. pernicious anemia or hemolysis.
but most patients with thyroid abnormalities are not anemic. 55] Even with the advent of better tests. 53. Patients with aplastic anemia will have a low WBC and/or platelet count. anemia can be a sign of bone marrow infiltration from lymphoma. It appears more commonly with advancing age and is rarely. Hb slowly. hypothyroidism may lead to macrocytosis without anemia. compared with only 9% in those with unexplained anemia. declined with aging. 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. Hypothyroidism and hyperthyroidism may be associated with pernicious anemia. The present data support unexplained anemia as distinct from anemia of chronic inflammation. 13.[5. the more severe the thyroid dysfunction. such as serum ferritin. Not uncommonly. Unexplained anemia in elderly persons The traditional notion has been that anemia in elderly persons always reflects a serious underlying condition. and soluble transferrin receptor. In a longitudinal study in healthy elderly subjects.  Occasionally. the mean CRP was 36. Thyroid disease Hypothyroidism reduces RBC mass and may lead to a normocytic anemia. Unexplained anemia is generally a condition of elderly persons. 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. [50. In elderly patients who reside in nursing homes. the more likely anemia will occur. Patients with myeloproliferative diseases often have an elevated WBC count.9 mg/dL for those with anemia of . however. methylmalonic acid. In these patients. A therapeutic trial correcting the thyroid abnormalities may be necessary to definitively determine their role in causing lower Hb concentration. Generally. the patient will not have palpable lymphadenopathy. a significant portion of elderly persons with anemia will be diagnosed as having unexplained anemia.Multiple myeloma should always be considered. Whether unexplained anemia represents a spectrum of undiagnosed etiologies or has a unifying pathogenesis remains unclear. a very high prevalence of unexplained anemia has been found (45%). 15.  and both conditions may also lead to a correctable anemia. encountered in younger adults. it has long been recognized that a proportion of patients. some patients with myelofibrosis will have anemia as the prominent abnormality. Finally. However. C-reactive protein (CRP) was elevated in 27% of patients who had anemia of chronic inflammation. if ever. In a nursing-home study categorizing anemia of chronic inflammation as the presence of an inflammatory comorbid condition. ranging from approximately 15-45%. 54. particularly in patients with elevated globulin levels. have anemia that does not meet diagnostic criteria for a specific etiology (unexplained anemia). but computed tomography (CT) scans could reveal extensive internal lymphadenopathy. 51] The degree of thyroid dysfunction leading to anemia remains unknown. measurement of a lactate dehydrogenase (LDH) level is essential. usually older. but predictably. 16. 14.
Another concern has been that unexplained anemia reflects occult myelodysplastic syndrome. whereas 3 patients had an unexplained macrocytic anemia (ie. A similar blunted EPO response occurs in patients with diabetes independent of reduced glomerular filtration.4). The expected inflammatory profile may be blunted. inadequate endogenous EPO secretion rather than a primary marrow problem leads to anemia. 39] Sex hormones The general Hb difference between men and women relates in large part to the erythropoietic effects of testosterone. [13. 64] Testosterone declines with aging in men.[8. administration of angiotensinconverting enzyme (ACE) medication may suppress EPO secretion and precipitate anemia. diabetes and hypertension) is blunted relative to those not having such a condition. a leukocyte count less than 3 K/uL. These included an MCV greater than 100 fL. children with nephritic syndrome. 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. Thus. have a blunted endogenous EPO response to anemia. high CRP) should alert the clinician to a possible inflammatory component. testosterone replacement raises Hb in older men. however. 17% of cases of unexplained anemia had hematologic abnormalities that may have been consistent with myelodysplastic syndrome. In a nursing home study. Although higher inflammatory markers have not been used as the sole criterion for the diagnosis of anemia of chronic inflammation. 57] In the National Health and Nutrition Examination Survey III (NHANES III) study of anemia in the elderly. or 10%.0 mg/dL for patients with unexplained anemia.8).2 g/dL to 1.5 pg/mL +/– 7.3 pg/mL +/– 72. the endogenous EPO response in those having renal-damaging conditions (ie. [60. A decline in renal function may be a feature of aging that is accentuated by hypertension and diabetes.chronic inflammation. compared with cases of unexplained anemia (8. Relative EPO deficiency In the prototypical model of complete renal failure.[8. Even in renal conditions without overt renal glomerular filtration abnormalities. with unexplained anemia). compared with 6. Finally. before significant renal clearance impairment. the presence of significant inflammation (ie. 27 patients exhibited a normocytic unexplained anemia. 15.5 g/dL on average. likely contributes to unexplained anemia. 3 of 30 patients. IL-6 levels were significantly higher in cases of anemia of chronic inflammation (44. Thus. The greater rate of Hb decline in men than in women with advancing age raises the suspicion that falling testosterone may cause unexplained anemia. endocrine function as measured by the endogenous EPO response to anemia may be impaired. . 61] In older adults with preserved renal function.[63. when patients are undergoing treatment for a chronic inflammatory disease. Hb falls by 1. For example. 66] Further. or a platelet count less than 150 K/uL. which can be illustrated by the fact that after orchiectomy or androgen deprivation therapy for prostate cancer. potentially from early renal damage. a relative EPO deficiency.
 and the proportion of unexplained anemia appeared similar in men and women. the highly heterogeneous nature of the elderly population has lead to multiple estimates of anemia prevalence in the elderly. Anemia Prevalence in the Elderly Based on WHO Criteria (Open Table in a new window) Study Age Population Guralnik et al. 2004 Most ≥65 Nursing home y Prevalence elderly. ≥71 y Community-dwelling 2007 Joosten et al. (See Table 2.) Table 2.A large epidemiologic study showed that men with lower testosterone were more likely to have anemia. Prevalence In addition to the varying thresholds for anemia. 11% 24% 24% (defined as Hb < 11. with a 5-year annual follow-up. ≥65 y Community-dwelling 2004 American Ferrucci et al. Multiple epidemiologic studies show an association between anemia or even mildly low Hb above the WHO threshold for anemia (ie. below. 74] Increased hospitalization[12. However. < 14 g/dL) and a worse outcome. ≥65 y Community-dwelling  2007 Italian Denny et al. 72.5 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. 70. 75] Increased difficulty with mobility[73. 78] Decreased activities of daily living and instrumental activities of daily living 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 26.7% of study participants who had anemia at baseline had more . One estimate suggests that more than 3 million elderly Americans are anemic. 73. 10. 72.6% elderly. ≥65 y Hospitalized 1992 Artz et al. 71. 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. 76] Falls[77. Prevalence estimates of anemia in elderly persons living in developing countries are lacking. 69. including the following: • • • • • • Increased mortality[12. one small study did not show a difference in testosterone between anemic and nonanemic older men.
disability in instrumental activities of daily living than did the other participants. 26] Sex Anemia in elderly persons is more common in men than in women. and 23% for those aged 85 years and older. Anemia is more common in black children. incident anemia during follow-up was associated with an additional increase in disability in basic activities of daily living. Also. This change is more pronounced in men. Some of the difference stems from employing a lower Hb threshold (eg. and Hb appears to decline similarly with advancing age in blacks and whites. part of the increased anemia prevalence relates to an alphathalassemia trait. 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. one study showed anemia prevalence was 8% among those aged 65-74 years.[19. Hb < 12 g/dL) for women than for men (ie. The causes for an acute fall in Hb are narrow (eg. < 13 g/dL). some of the disparity is likely related to biologic differences. [19. Transfusion history . hemolysis). as opposed to the more common slow decline over time. 13% for those aged 75-84 years. Among community-dwelling adults aged 65 years and older. with the median Hb for elderly blacks being approximately 0. 26] Older Mexican Americans have a fairly similar prevalence of anemia to that of elderly whites. Age Hb declines slightly and anemia prevalence rises in men and women with advancing age. Elderly persons have frequently had previous blood counts that are easily retrievable. Whether anemia has different adverse consequences in blacks is unclear.8 g/dL lower than for whites. bleeding. The cause for the higher prevalence of anemia in blacks has not been established. Epidemiology Race Anemia is approximately 3 times more prevalent in elderly blacks than it is in non-Hispanic whites. The reason for increased anemia prevalence with advancing age has not been established. In younger adults. However. Moreover. prevalent and incident anemia were associated with an increased risk of death.
to gather additional objective information is often useful. as well as marrow hypoproliferation and gastrointestinal bleeding. The anemia is often the consequence of multiple phlebotomies. such as walking up stairs. cancer (and cancer chemotherapy. Alcohol overuse may go unrecognized in the elderly and leads to deficiencies of vitamin B-12 and folate. Recent surgery suggests blood loss and necessitates comparison to preoperative Hb values. a detailed history often identifies the presence of anemia-related symptoms. or both. Racial background Family history can be useful for considering a coexistent thalassemia trait or other hemoglobinopathy. Diseases that frequently cause anemia should be noted. Inquiring about specific tasks. Medical history Recent hospitalization often results in anemia. Symptoms Symptoms relate to the rapidity of the anemia. infection. chronic kidney disease. tinnitus).One should inquire whether RBC transfusions have previously been administered. the prehospitalization Hb can be invaluable. had another condition preventing an appropriate response to blood loss. with a recognition that blacks may have approximately 0. particularly in elderly persons. including myelodysplasia. Lymphoproliferative and autoimmune disease may cause autoimmune hemolytic anemia.8 g/dL less Hb than whites. the patient has often had a preexisting low Hb before the surgery. Previous chemotherapy or radiotherapy raises the possibility of therapy-related myelodysplastic syndrome. Ancestry should be considered. End-stage renal disease (ESRD) uniformly causes anemia. and concomitant medical conditions. A history of transfusions will alert the clinician to a chronic problem. Special attention should be paid to elements that indicate a cause for the anemia (eg. . gastrointestinal blood loss. as well as the acute illness itself. The nonspecific nature of anemia-related symptoms poses a major challenge. Patients may mistakenly attribute decreased energy to aging or other medications. Thus. and rheumatologic disorders. the depth of the Hb fall. unless an erythropoietinstimulating agent is administered. arthritis) and symptoms related to anemia (fatigue. Nevertheless. presence or symptoms of cancer. When surgery requires RBC transfusion. Conditions that are associated with specific types of anemia should be clearly identified. especially myelosuppressive chemotherapy). shortness of breath.
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. hemoptysis. the examination must be comprehensive. melena. hematemesis). however. Blood loss should be directly inquired about (eg.Most symptoms of anemia are nonspecific. hematuria) Pica (desire to consume unusual substances. signs related to the anemia. Thus. hematuria. a temporal relation between falling Hb and symptom exacerbation is very useful. 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. Special attention should be paid to the following: • • • • • • • • • Pallor Icterus Lymphadenopathy Tachycardia Cardiac murmurs Hepatomegaly Splenomegaly Edema Stool for color . or both. red blood in the stools.
or peripheral smear. Several common facts guide the evaluation. They are often based on kinetic measures made by first assessing the reticulocyte count. as follows: • • Most anemia in elderly persons is hypoproliferative (ie. 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. Such an investigation must account for the unique epidemiology in this population.• 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. malignancy. RBC size (using the MCV). the more likely an obvious and/or serious cause will be detected . reticulocytosis is inadequately low) Generally. the more severe the anemia.
the blood counts should be reevaluated after identifying the problem. Once a deficiency is identified. especially if total globulins are elevated In about two thirds of elderly persons with anemia. Recommended studies include the following: • • • • • • • • • • • • CBC count (with WBC differential. correcting the deficiency. 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. this initial evaluation will lead to a presumed etiology for the anemia. < 12 g/dL for women) Hb that has fallen more than 2 g/dL over any period without an adequate explanation (eg. 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 . or both. 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. 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. a comprehensive evaluation is useful. platelet count. A reiterative process is essential.• • • • Previous blood counts are often available Approximately one third of older subjects will have an unexplained anemia.
Low serum ferritin (eg. complicating the diagnosis of iron deficiency anemia in the presence of inflammation. serum iron. every elderly anemic adult requires a thorough evaluation to determine the underlying cause of iron deficiency. Intermediate ferritin values between 18 and 44 ng/mL are highly suggestive of iron deficiency in the elderly. the more likely a specific cause will be identified. That said. A major pitfall is misinterpreting the MCV. nor does a normocytic anemia exclude iron deficiency. 83] and ferritin values above 100 ng/dL make iron deficiency highly unlikely.5 g/dL). the MCV is an average of all the RBCs analyzed. Although microcytosis occurs in iron deficiency anemia. absent an obvious chronic inflammatory disease. This generally requires a hematology or pathology review. Peripheral blood smear A peripheral blood smear is invaluable. alcohol use or liver disease leads to increased RBC size. soluble transferrin receptor (sTFR). reticulocyte Hb content. microcytosis is a late finding and typically occurs only after chronic iron deficiency.) Androgen insufficiency may be evaluated with a testosterone level. a hematology referral and/or bone marrow examination should be considered. . including malignancy. serum transferrin.• • Urine Hb Urine hemosiderin (Splenic ultrasonography. and bone marrow examination. < 12 ng/mL) is highly specific for iron deficiency anemia. serum ferritin. ferritin can be elevated in inflammation. is highly suspicious for iron deficiency (eg. including RBC MCV.  Thus. erythrocyte protoporphyrin. a developing microcytic anemia in an older adult. As an acute phase reactant. rather than a technician-reported analysis of the peripheral smear. especially when determining if a primary bone marrow process accounts for macrocytic anemia. The impact of other factors may abrogate the standard changes in cell size. Numerous tests are available to diagnose iron deficiency. The more severe the anemia and the more severe the macrocytosis. [82. iron saturation. Because iron deficiency is correctable and often reflects gastrointestinal pathology. 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. 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. an imaging test. Further. For example. Iron deficiency occurs in approximately 20% of elderly anemic patients. 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. can also be used in the evaluation of hemolysis. leading to an Hb value of less than 10 g/dL.
malabsorption) should be investigated and vitamin B-12 replenished. Once must be careful not to judge the patient’s wishes.[83. evaluate methylmalonic acid. should iron deficiency be suspected.Alternative strategies to diagnose iron deficiency anemia have been studied. serum ferritin remains the standard test to exclude iron deficiency in the elderly. in addition to cost and inconvenience.[87. The lack of laboratory standardization in reporting or a standardized value that is diagnostic of iron deficiency further complicates the use of sTFR. a thorough endoscopic evaluation is often necessary rather than only prescribing iron replacement. if iron stores are adequate and the anemia persists. For example. pernicious anemia should be considered in patients with vitamin B-12 deficiency. Unless acute bleeding is occurring. If a level of less than 200 pg/mL is detected. sTFR is less sensitive in detecting early iron deficiency compared with ferritin. a ratio greater than 2. The sTFR is a truncated fragment of the membrane receptor that is increased in iron deficiency. Thus. then etiologies of vitamin B-12 deficiency (eg. if ever. and clinicians should approach the patient and family with the options. Evaluation of Vitamin B-12 and Folate Deficiencies Vitamin B-12 and folate deficiencies are uncommon. Low vitamin B-12 levels are frequent in older adults. when iron availability for erythropoiesis is low. identify the cause of the anemia in elderly persons. An elevated . as these conditions are treatable and usually highlight the presence of another condition. Another method standardizes sTFR based on the serum ferritin. Alternatively. Occasionally the patient is too ill or the family does not desire an evaluation. 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. such as a level between 200 and 350 pg/mL. Bone marrow evaluation has been considered the criterion standard for iron deficiency. 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. but they are essential to exclude as causes of anemia. an endoscopic evaluation will rarely. bone marrow examinations can be highly misleading and may require up to 7-9 aspirate smears to confidently prove iron stores are absent. 85] Further. However. 88] Thus. raising the threshold of ferritin to less than 30-50 ng/mL affords a similar or better diagnostic performance. By using the log of the sTFR/ferritin. most commonly employing the sTFR. Folate deficiency has become very uncommon with routine supplementation. pernicious anemia. However.5 may indicate iron deficiency. gastrointestinal bleeding causes anemia through iron deficiency.
Homocysteine is elevated in vitamin B-12 deficiency and folate deficiency. An MCV greater than 95-100 fL defines macrocytosis. bone pain. The threshold to pursue a bone marrow examination to exclude myelodysplastic syndromes remains unknown. However. because serum EPO should rise with declining Hb values. hydroxyurea. Macrocytosis. Potential causes for macrocytic anemia include the following: • • • • Vitamin B-12 deficiency Folate deficiency Medications (myelosuppressive anticonvulsants) Alcohol overuse chemotherapy. which indicates that the low nutrient level was not causative. It is clear that this anemia is typically associated with a low serum EPO level for the degree of anemia. normocytic. early satiety. One must recognize that methylmalonic acid is elevated in renal dysfunction. the anemia does not correct. . this finding is abnormal. 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. or unexplained constitutional symptoms of fever. thrombocytopenia. the authors advocate considering a bone marrow examination in all patients who required RBC transfusion who otherwise have an unexplained anemia. trimethoprim. occult inflammation. and myelodysplastic syndromes. neutropenia. 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 diagnosis of unexplained anemia assumes the clinician has excluded serious causes. and hypoproliferative [low reticulocyte count]). Anemia due to vitamin B-12 or folate deficiency need not be macrocytic. Potential explanations for the anemia have included low testosterone. If the methylmalonic acid is elevated in the setting of anemia and a low vitamin B-12. inappropriately low serum EPO level. reduced hematopoietic reserve with advancing age.methylmalonic acid level is evidence of a vitamin B-12 tissue deficiency. or weight loss should prompt consideration of a bone marrow examination. However. Normal laboratory ranges for MCV vary. However. The EPO level usually falls within the normal reference range. This anemia is generally mild (Hb from 9-12 g/dL. as this more often reflects other conditions or bone marrow pathology. Reevaluating the anemia after treatment is essential. Commonly. Evaluation of Macrocytic Anemia Macrocytic anemia in older adults truly demands a thoughtful investigation of potential causes. the presence of an MCV greater than 115 fL is highly suspicious for the megaloblastoid anemia that is seen with these deficiencies. Evaluation of Unexplained Anemia Increasingly. splenomegaly. evaluate for vitamin B-12 deficiency and empirically treat the patient. chills.
Gaucher disease). Occasionally. RBC transfusion is warranted. MDS. Erythropoiesis-Stimulating Agents Erythropoiesis-stimulating agents (ESAs) approved in the United States include epoetin-alfa (Procrit. RBC Transfusion For severe anemia. transfusion reactions. In light of the increased risk of thrombosis. the risks and benefits associated with the treatment in patients with chronic kidney disease. An ultrasonogram of the left upper quadrant can be helpful if the patient's body habitus makes examination for splenomegaly difficult. MDS should be diagnosed based on a bone marrow examination and not only on the peripheral smear.• • • • • • • Liver disease Hypothyroidism Chronic obstructive pulmonary disease Reticulocytosis Spurious (eg. Transfusions entail numerous. and. lymphoma). hyperglycemia or cold agglutinin disease) Marrow disease. the marrow is used to accurately gauge iron stores. Transfusing 2 units of RBCs may represent a considerable volume for elderly patients who have preexisting cardiac dysfunction. particularly older adults not on dialysis and not receiving RBC transfusions. Because of concerns about increased mortality when using a liberal transfusion policy. progression of certain cancers associated with ESA use in a population at increased danger for such events. 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). potentially. or consider nonmalignant marrow processes (eg. hypertension. The need for transfusion is also related to the rapidity of the Hb drop. Repeated transfusions can result in iron overload and clinical manifestations of hemochromatosis. aplastic anemia) is suspected. Bone marrow examination generally has fewer complications and is less invasive than generally appreciated. The primary indications are for anemia due to chronic kidney disease or cancer chemotherapy. remain unexplored. 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. as patients will be more symptomatic from a more acute drop in Hb. risks of infection. especially myelodysplastic syndromes Cold agglutinin disease Other Tests A bone marrow aspirate and biopsy are used when a primary marrow disease (eg. Recommendations for Hb thresholds below which RBC transfusions should be given vary from 5-10 g/dL. infection. and costs. entertain marrow involvement of nonmarrow diseases (eg. . volume overload. hemophagocytic syndrome. and often underappreciated. Epogen) and darbepoetin-alfa (Aranesp).
[90. 91] Iron supplementation is frequently needed to prevent iron-restricted erythropoiesis once an elderly patient is on ESA treatment. and if a clear quality-of-life improvement can be measured. if the patient or caregiver understands the risks. 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. assuming all other etiologies have been excluded. . Prescribing of ESAs should be restricted to physicians experienced in the use and monitoring of such treatment. The authors generally use an ESA for anemia due to chronic kidney disease to obviate RBC transfusions. The authors will consider ESA therapy for anemia of chronic kidney disease if the Hb is less than 10 g/dL. if the patient can be monitored closely for complications.caution must be exercised.
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