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.

Anemia Thresholds
In the vast majority of patients, Hb represents an excellent and easily reproducible measure of RBC mass. The Hb value below which anemia is defined varies. 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. [10] The threshold has been widely criticized based upon an association of adverse outcomes with higher Hb concentrations.[11, 12] However, the WHO criteria remain useful to compare anemia prevalence in different studies. Hb thresholds for anemia may be defined distinctly for various reasons; thus, different thresholds are considered:

Prognostic marker: Numerous studies have shown that mildly low Hb values, often 12 g/dL above the WHO threshold, have been associated with increased mortality, hospitalization, and functional decline in elderly persons. Etiologic marker: Clinicians most often define anemia to determine if an etiologic evaluation should be pursued. A wealth of data shows that important causes are uncovered if an evaluation is performed for anemia as defined by the WHO threshold. Treatment: A lower Hb threshold is often used when deciding whether to treat with pharmacologic erythropoietin or RBC transfusions.

Etiology
Multiple conditions can lead to anemia in elderly persons. (See Table 1, below.) Moreover, the anemia may be multifactorial. Nevertheless, in the majority of cases of anemia in elderly persons, an etiology can be found. The most common causes include iron deficiency (with or without blood loss), chronic disease/inflammation, and chronic kidney disease.[13, 14, 15, 16] Other etiologies of anemia in the elderly include deficiencies of folate or vitamin B-12, diseases of the bone marrow (eg, myelodysplastic syndromes, aplastic anemia, paroxysmal nocturnal hemoglobinuria, myeloproliferative syndromes, acute or chronic leukemia, lymphoma), hypothyroidism, hypersplenism, and hemolytic anemia. Despite a complete evaluation, a significant minority of cases have no etiology uncovered (ie, unexplained anemia).[14, 15] Table 1. 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%

Iron deficiency anemia

Identifying iron deficiency anemia in elderly persons is essential, and the condition can be corrected. More importantly, iron deficiency, particularly in elderly persons, often points to an underlying gastrointestinal pathology, including malignancy. [17, 18] Despite the importance of establishing a diagnosis, iron deficiency anemia represents only 15-23% of cases of anemia among the elderly.[13, 14, 15]

Anemia of chronic disease and inflammation

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

Renal insufficiency
Chronic kidney disease is an important cause of anemia in elderly persons, especially considering that renal function declines with aging.[33, 34] Reduced renal EPO production is the

primary factor leading to anemia in chronic kidney disease. Serum EPO levels have been shown to be inappropriately low at a creatinine clearance of less than 40 mL/min. [35, 36] The precise degree of renal dysfunction sufficient to cause anemia remains controversial. Mild Hb decreases in adults may be detected at a creatinine clearance of 40-60 mL/min.[37, 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.[39] Renal function in older residents in a skilled nursing facility was also examined,[40] and 43% had chronic kidney disease (defined as a creatinine clearance of less than 60 mL/min). Chronic kidney disease increased the risk of anemia.

Nutrient deficiencies
Low vitamin B-12 levels in elderly persons are not uncommon. However, vitamin B-12 deficiency is a very uncommon cause of anemia in elderly persons.[41] Folate deficiency is also uncommon, in part related to widespread vitamin supplementation.[42] To the extent that such mineral deficiencies are reversible and suggest other conditions (eg, pernicious anemia or hemolysis, respectively), they remain important to identify.

Myelodysplastic syndromes
Myelodysplastic syndromes represent a heterogeneous group of disorders characterized by clonal hematopoiesis and peripheral blood cytopenias. They are more common in older adults and may present as an isolated anemia. In the elderly, anemia in conjunction with macrocytosis, thrombocytopenia, or neutropenia absent another cause raises the suspicion of myelodysplastic syndrome.[43, 44] Alternatively, myelodysplastic syndrome is an unlikely cause of idiopathic normocytic anemia in elderly persons.[45, 46, 47] When evaluating mean corpuscular volume (MCV), one must be cognizant that recent RBC transfusions will alter the values. Thus, retrieving hematology values before a transfusion is critical.

Other primary hematologic disorders

A variety of other primary hematologic disorders have anemia as a manifestation. Thrombotic thrombocytopenic purpura (TTP), although rare, should be considered in every patient with anemia, as this a medical emergency requiring prompt intervention. Often (but not always), patients will have other cardinal features of the disease, including thrombocytopenia, altered mental status, and renal insufficiency. Elderly patients with acute leukemia can have a more smoldering disease course than younger patients. These patients may present with a low, high, or even normal white blood cell (WBC) count, although in most individuals the WBC differential is abnormal. This fact emphasizes the importance of performing a manual differential in all patients with an abnormal complete blood count (CBC). Chronic lymphocytic leukemia (CLL) is common in elderly persons. Although most patients will have either an elevated WBC count or lymphadenopathy at presentation, some patients will present with autoimmune hemolytic anemia and could have relatively little evidence of CLL.

Multiple myeloma should always be considered, particularly in patients with elevated globulin levels. Patients with aplastic anemia will have a low WBC and/or platelet count. Patients with myeloproliferative diseases often have an elevated WBC count; however, some patients with myelofibrosis will have anemia as the prominent abnormality. Finally, anemia can be a sign of bone marrow infiltration from lymphoma. Not uncommonly, the patient will not have palpable lymphadenopathy, but computed tomography (CT) scans could reveal extensive internal lymphadenopathy. In these patients, measurement of a lactate dehydrogenase (LDH) level is essential.

Thyroid disease
Hypothyroidism reduces RBC mass and may lead to a normocytic anemia. [48] Occasionally, hypothyroidism may lead to macrocytosis without anemia.[49] Hypothyroidism and hyperthyroidism may be associated with pernicious anemia, [50] and both conditions may also lead to a correctable anemia, but most patients with thyroid abnormalities are not anemic. [50, 51] The degree of thyroid dysfunction leading to anemia remains unknown. Generally, the more severe the thyroid dysfunction, the more likely anemia will occur. A therapeutic trial correcting the thyroid abnormalities may be necessary to definitively determine their role in causing lower Hb concentration.

Unexplained anemia in elderly persons

The traditional notion has been that anemia in elderly persons always reflects a serious underlying condition.[52] However, it has long been recognized that a proportion of patients, usually older, have anemia that does not meet diagnostic criteria for a specific etiology (unexplained anemia). 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, ranging from approximately 15-45%.[5, 13, 14, 15, 16, 53, 54, 55] Even with the advent of better tests, such as serum ferritin, methylmalonic acid, and soluble transferrin receptor, a significant portion of elderly persons with anemia will be diagnosed as having unexplained anemia.[15] Unexplained anemia is generally a condition of elderly persons. It appears more commonly with advancing age and is rarely, if ever, encountered in younger adults.[56] In a longitudinal study in healthy elderly subjects, Hb slowly, but predictably, declined with aging.[8] In elderly patients who reside in nursing homes, a very high prevalence of unexplained anemia has been found (45%).[15] Whether unexplained anemia represents a spectrum of undiagnosed etiologies or has a unifying pathogenesis remains unclear. The present data support unexplained anemia as distinct from anemia of chronic inflammation. Guralnik and colleagues evaluated data from community-dwelling elderly and defined anemia of chronic inflammation as a serum iron less than 60 g/dL but without iron deficiency.[13] C-reactive protein (CRP) was elevated in 27% of patients who had anemia of chronic inflammation, compared with only 9% in those with unexplained anemia. In a nursing-home study categorizing anemia of chronic inflammation as the presence of an inflammatory comorbid condition, the mean CRP was 36.9 mg/dL for those with anemia of

chronic inflammation, compared with 6.0 mg/dL for patients with unexplained anemia. IL-6 levels were significantly higher in cases of anemia of chronic inflammation (44.3 pg/mL +/ 72.4), compared with cases of unexplained anemia (8.5 pg/mL +/ 7.8). Thus, 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. Although higher inflammatory markers have not been used as the sole criterion for the diagnosis of anemia of chronic inflammation, the presence of significant inflammation (ie, high CRP) should alert the clinician to a possible inflammatory component. The expected inflammatory profile may be blunted, however, when patients are undergoing treatment for a chronic inflammatory disease. Another concern has been that unexplained anemia reflects occult myelodysplastic syndrome. [13, 57] In the National Health and Nutrition Examination Survey III (NHANES III) study of anemia in the elderly, 17% of cases of unexplained anemia had hematologic abnormalities that may have been consistent with myelodysplastic syndrome.[13] These included an MCV greater than 100 fL, a leukocyte count less than 3 K/uL, or a platelet count less than 150 K/uL. In a nursing home study, 27 patients exhibited a normocytic unexplained anemia, whereas 3 patients had an unexplained macrocytic anemia (ie, 3 of 30 patients, or 10%, with unexplained anemia).[15]

Relative EPO deficiency

In the prototypical model of complete renal failure, inadequate endogenous EPO secretion rather than a primary marrow problem leads to anemia.[36] Even in renal conditions without overt renal glomerular filtration abnormalities, endocrine function as measured by the endogenous EPO response to anemia may be impaired. For example, children with nephritic syndrome, before significant renal clearance impairment, have a blunted endogenous EPO response to anemia.[58] A similar blunted EPO response occurs in patients with diabetes independent of reduced glomerular filtration.[59] Finally, administration of angiotensinconverting enzyme (ACE) medication may suppress EPO secretion and precipitate anemia. [60,
61]

In older adults with preserved renal function, the endogenous EPO response in those having renal-damaging conditions (ie, diabetes and hypertension) is blunted relative to those not having such a condition.[8] A decline in renal function may be a feature of aging that is accentuated by hypertension and diabetes.[62] Thus, a relative EPO deficiency, potentially from early renal damage, likely contributes to unexplained anemia.[8, 15, 39]

Sex hormones
The general Hb difference between men and women relates in large part to the erythropoietic effects of testosterone, which can be illustrated by the fact that after orchiectomy or androgen deprivation therapy for prostate cancer, Hb falls by 1.2 g/dL to 1.5 g/dL on average.[63, 64] Testosterone declines with aging in men.[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.[8, 66] Further, testosterone replacement raises Hb in older men.[67]

A large epidemiologic study showed that men with lower testosterone were more likely to have anemia. However, one small study did not show a difference in testosterone between anemic and nonanemic older men,[45] and the proportion of unexplained anemia appeared similar in men and women.[13]

Prevalence
In addition to the varying thresholds for anemia, the highly heterogeneous nature of the elderly population has lead to multiple estimates of anemia prevalence in the elderly. One estimate suggests that more than 3 million elderly Americans are anemic.[13] (See Table 2, below.) Table 2. Anemia Prevalence in the Elderly Based on WHO Criteria (Open Table in a new window) Study Age Population Guralnik et al, 65 y Community-dwelling 2004[13] American Ferrucci et al, 65 y Community-dwelling [68] 2007 Italian Denny et al, 71 y Community-dwelling 2007[69] Joosten et al, 65 y Hospitalized 1992[14] Artz et al, 2004[15] Most 65 Nursing home y Prevalence elderly, 10.6% elderly, 11% 24% 24% (defined as Hb < 11.5 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. Prevalence estimates of anemia in elderly persons living in developing countries are lacking.

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. Multiple epidemiologic studies show an association between anemia or even mildly low Hb above the WHO threshold for anemia (ie, < 14 g/dL) and a worse outcome, including the following:

Increased mortality[12, 69, 70, 71, 72, 73, 74] Increased hospitalization[12, 72, 75] Increased difficulty with mobility[73, 76] Falls[77, 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, with a 5-year annual follow-up, den Elzen et al found that the 26.7% of study participants who had anemia at baseline had more

disability in instrumental activities of daily living than did the other participants.[79] Also, incident anemia during follow-up was associated with an additional increase in disability in basic activities of daily living.[79] Moreover, prevalent and incident anemia were associated with an increased risk of death.

Epidemiology
Race
Anemia is approximately 3 times more prevalent in elderly blacks than it is in non-Hispanic whites, with the median Hb for elderly blacks being approximately 0.8 g/dL lower than for whites.[19, 26] Older Mexican Americans have a fairly similar prevalence of anemia to that of elderly whites. The cause for the higher prevalence of anemia in blacks has not been established. However, some of the disparity is likely related to biologic differences. Anemia is more common in black children,[33] and Hb appears to decline similarly with advancing age in blacks and whites.[19] In younger adults, part of the increased anemia prevalence relates to an alphathalassemia trait.[34] Whether anemia has different adverse consequences in blacks is unclear.
[19, 26]

Sex
Anemia in elderly persons is more common in men than in women. Some of the difference stems from employing a lower Hb threshold (eg, Hb < 12 g/dL) for women than for men (ie, < 13 g/dL).

Age
Hb declines slightly and anemia prevalence rises in men and women with advancing age.[8] This change is more pronounced in men. Among community-dwelling adults aged 65 years and older, one study showed anemia prevalence was 8% among those aged 65-74 years, 13% for those aged 75-84 years, and 23% for those aged 85 years and older.[13] The reason for increased anemia prevalence with advancing age has not been established.

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. The causes for an acute fall in Hb are narrow (eg, bleeding, hemolysis), as opposed to the more common slow decline over time. Elderly persons have frequently had previous blood counts that are easily retrievable.

Transfusion history

One should inquire whether RBC transfusions have previously been administered. A history of transfusions will alert the clinician to a chronic problem.

Medical history
Recent hospitalization often results in anemia, particularly in elderly persons. The anemia is often the consequence of multiple phlebotomies, as well as the acute illness itself. Thus, the prehospitalization Hb can be invaluable. Recent surgery suggests blood loss and necessitates comparison to preoperative Hb values. When surgery requires RBC transfusion, the patient has often had a preexisting low Hb before the surgery, had another condition preventing an appropriate response to blood loss, or both. Diseases that frequently cause anemia should be noted, including myelodysplasia, cancer (and cancer chemotherapy, especially myelosuppressive chemotherapy), chronic kidney disease, and rheumatologic disorders. End-stage renal disease (ESRD) uniformly causes anemia, unless an erythropoietinstimulating agent is administered. Conditions that are associated with specific types of anemia should be clearly identified. Lymphoproliferative and autoimmune disease may cause autoimmune hemolytic anemia. Previous chemotherapy or radiotherapy raises the possibility of therapy-related myelodysplastic syndrome. Alcohol overuse may go unrecognized in the elderly and leads to deficiencies of vitamin B-12 and folate, as well as marrow hypoproliferation and gastrointestinal bleeding.

Racial background
Family history can be useful for considering a coexistent thalassemia trait or other hemoglobinopathy. Ancestry should be considered, with a recognition that blacks may have approximately 0.8 g/dL less Hb than whites.

Symptoms
Symptoms relate to the rapidity of the anemia, the depth of the Hb fall, and concomitant medical conditions. The nonspecific nature of anemia-related symptoms poses a major challenge. Nevertheless, a detailed history often identifies the presence of anemia-related symptoms. Inquiring about specific tasks, such as walking up stairs, to gather additional objective information is often useful. Patients may mistakenly attribute decreased energy to aging or other medications. Special attention should be paid to elements that indicate a cause for the anemia (eg, presence or symptoms of cancer, gastrointestinal blood loss, infection, arthritis) and symptoms related to anemia (fatigue, shortness of breath, tinnitus).

Most symptoms of anemia are nonspecific; however, a temporal relation between falling Hb and symptom exacerbation is very useful. Blood loss should be directly inquired about (eg, melena, hematuria, hemoptysis, hematemesis). 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, red blood in the stools, hematuria) Pica (desire to consume unusual substances, 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, or both. Thus, the examination must be comprehensive. Special attention should be paid to the following:

Pallor Icterus Lymphadenopathy Tachycardia Cardiac murmurs Hepatomegaly Splenomegaly Edema Stool for color

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, 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. They are often based on kinetic measures made by first assessing the reticulocyte count, RBC size (using the MCV), or peripheral smear. Such an investigation must account for the unique epidemiology in this population. Several common facts guide the evaluation, as follows:

Most anemia in elderly persons is hypoproliferative (ie, reticulocytosis is inadequately low) Generally, the more severe the anemia, the more likely an obvious and/or serious cause will be detected

Previous blood counts are often available Approximately one third of older subjects will have an unexplained anemia, 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; < 12 g/dL for women) Hb that has fallen more than 2 g/dL over any period without an adequate explanation (eg, 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. Recommended studies include the following:

CBC count (with WBC differential, platelet count, 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, especially if total globulins are elevated

In about two thirds of elderly persons with anemia, this initial evaluation will lead to a presumed etiology for the anemia. A reiterative process is essential. Once a deficiency is identified, the blood counts should be reevaluated after identifying the problem, correcting the deficiency, or both. 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

Urine Hb Urine hemosiderin

(Splenic ultrasonography, an imaging test, can also be used in the evaluation of hemolysis.) Androgen insufficiency may be evaluated with a testosterone level.

Peripheral blood smear

A peripheral blood smear is invaluable, especially when determining if a primary bone marrow process accounts for macrocytic anemia. This generally requires a hematology or pathology review, rather than a technician-reported analysis of the peripheral smear. If no cause is identified, a hematology referral and/or bone marrow examination should be considered. The more severe the anemia and the more severe the macrocytosis, the more likely a specific cause will be identified.

Evaluation of Iron Deficiency

Serum iron is not an adequate test to exclude iron deficiency, nor does a normocytic anemia exclude iron deficiency. Iron deficiency occurs in approximately 20% of elderly anemic patients. Because iron deficiency is correctable and often reflects gastrointestinal pathology, including malignancy, every elderly anemic adult requires a thorough evaluation to determine the underlying cause of iron deficiency. Numerous tests are available to diagnose iron deficiency, including RBC MCV, serum iron, serum transferrin, iron saturation, serum ferritin, soluble transferrin receptor (sTFR), reticulocyte Hb content, erythrocyte protoporphyrin, and bone marrow examination. Serum ferritin is the most useful test for diagnosing iron deficiency anemia. Low serum ferritin (eg, < 12 ng/mL) is highly specific for iron deficiency anemia.[80] As an acute phase reactant, ferritin can be elevated in inflammation, complicating the diagnosis of iron deficiency anemia in the presence of inflammation.[81] Intermediate ferritin values between 18 and 44 ng/mL are highly suggestive of iron deficiency in the elderly, [82, 83] and ferritin values above 100 ng/dL make iron deficiency highly unlikely. [83] Thus, 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. A major pitfall is misinterpreting the MCV. Although microcytosis occurs in iron deficiency anemia, microcytosis is a late finding and typically occurs only after chronic iron deficiency, leading to an Hb value of less than 10 g/dL. Further, the MCV is an average of all the RBCs analyzed. The impact of other factors may abrogate the standard changes in cell size. For example, alcohol use or liver disease leads to increased RBC size. That said, a developing microcytic anemia in an older adult, absent an obvious chronic inflammatory disease, is highly suspicious for iron deficiency (eg, an initial MCV of 85 and an Hb of 12 g/dL changes to an MCV of 75 and an Hb of 9.5 g/dL).

Alternative strategies to diagnose iron deficiency anemia have been studied, most commonly employing the sTFR. The sTFR is a truncated fragment of the membrane receptor that is increased in iron deficiency, when iron availability for erythropoiesis is low. STFR enhances diagnostic sensitivity in elderly persons compared with using a very low serum ferritin for iron deficiency anemia.[84] Another method standardizes sTFR based on the serum ferritin. By using the log of the sTFR/ferritin, a ratio greater than 2.5 may indicate iron deficiency. However, raising the threshold of ferritin to less than 30-50 ng/mL affords a similar or better diagnostic performance.[83, 85] Further, sTFR is less sensitive in detecting early iron deficiency compared with ferritin.[86] The lack of laboratory standardization in reporting or a standardized value that is diagnostic of iron deficiency further complicates the use of sTFR. Bone marrow evaluation has been considered the criterion standard for iron deficiency. However, in addition to cost and inconvenience, bone marrow examinations can be highly misleading and may require up to 7-9 aspirate smears to confidently prove iron stores are absent.[87, 88] Thus, serum ferritin remains the standard test to exclude iron deficiency in the elderly. 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. Unless acute bleeding is occurring, gastrointestinal bleeding causes anemia through iron deficiency. Thus, if iron stores are adequate and the anemia persists, an endoscopic evaluation will rarely, if ever, identify the cause of the anemia in elderly persons. Alternatively, should iron deficiency be suspected, a thorough endoscopic evaluation is often necessary rather than only prescribing iron replacement. Occasionally the patient is too ill or the family does not desire an evaluation. Once must be careful not to judge the patients wishes, 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, but they are essential to exclude as causes of anemia, as these conditions are treatable and usually highlight the presence of another condition. For example, pernicious anemia should be considered in patients with vitamin B-12 deficiency. Folate deficiency has become very uncommon with routine supplementation. Low vitamin B-12 levels are frequent in older adults. If a level of less than 200 pg/mL is detected, then etiologies of vitamin B-12 deficiency (eg, pernicious anemia, malabsorption) should be investigated and vitamin B-12 replenished. For equivocal levels of vitamin B-12, such as a level between 200 and 350 pg/mL, evaluate methylmalonic acid. An elevated

methylmalonic acid level is evidence of a vitamin B-12 tissue deficiency. One must recognize that methylmalonic acid is elevated in renal dysfunction. Homocysteine is elevated in vitamin B-12 deficiency and folate deficiency. If the methylmalonic acid is elevated in the setting of anemia and a low vitamin B-12, evaluate for vitamin B-12 deficiency and empirically treat the patient. Reevaluating the anemia after treatment is essential. Commonly, the anemia does not correct, which indicates that the low nutrient level was not causative. Anemia due to vitamin B-12 or folate deficiency need not be macrocytic. However, 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, it has become recognized that approximately one third of older adults do not have an obviously discernible cause of anemia upon an extensive evaluation. This anemia is generally mild (Hb from 9-12 g/dL, normocytic, and hypoproliferative [low reticulocyte count]). Potential explanations for the anemia have included low testosterone, occult inflammation, reduced hematopoietic reserve with advancing age, inappropriately low serum EPO level, and myelodysplastic syndromes. It is clear that this anemia is typically associated with a low serum EPO level for the degree of anemia. The EPO level usually falls within the normal reference range. However, this finding is abnormal, because serum EPO should rise with declining Hb values. The diagnosis of unexplained anemia assumes the clinician has excluded serious causes. The threshold to pursue a bone marrow examination to exclude myelodysplastic syndromes remains unknown. However, the authors advocate considering a bone marrow examination in all patients who required RBC transfusion who otherwise have an unexplained anemia. Macrocytosis, thrombocytopenia, neutropenia, splenomegaly, or unexplained constitutional symptoms of fever, chills, early satiety, bone pain, or weight loss should prompt consideration of a bone marrow examination.

Evaluation of Macrocytic Anemia

Macrocytic anemia in older adults truly demands a thoughtful investigation of potential causes, as this more often reflects other conditions or bone marrow pathology. Normal laboratory ranges for MCV vary. An MCV greater than 95-100 fL defines macrocytosis. 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. Potential causes for macrocytic anemia include the following:

Vitamin B-12 deficiency Folate deficiency Medications (myelosuppressive anticonvulsants) Alcohol overuse

chemotherapy,

hydroxyurea,

trimethoprim,

Liver disease Hypothyroidism Chronic obstructive pulmonary disease Reticulocytosis Spurious (eg, hyperglycemia or cold agglutinin disease) Marrow disease, especially myelodysplastic syndromes Cold agglutinin disease

Other Tests
A bone marrow aspirate and biopsy are used when a primary marrow disease (eg, MDS, aplastic anemia) is suspected. Occasionally, the marrow is used to accurately gauge iron stores, entertain marrow involvement of nonmarrow diseases (eg, infection, lymphoma), or consider nonmalignant marrow processes (eg, hemophagocytic syndrome, Gaucher disease). MDS should be diagnosed based on a bone marrow examination and not only on the peripheral smear. Bone marrow examination generally has fewer complications and is less invasive than generally appreciated. An ultrasonogram of the left upper quadrant can be helpful if the patient's body habitus makes examination for splenomegaly difficult.

RBC Transfusion
For severe anemia, RBC transfusion is warranted. Transfusions entail numerous, and often underappreciated, risks of infection, volume overload, transfusion reactions, and costs. Transfusing 2 units of RBCs may represent a considerable volume for elderly patients who have preexisting cardiac dysfunction. Repeated transfusions can result in iron overload and clinical manifestations of hemochromatosis. Recommendations for Hb thresholds below which RBC transfusions should be given vary from 5-10 g/dL. The need for transfusion is also related to the rapidity of the Hb drop, as patients will be more symptomatic from a more acute drop in Hb. Because of concerns about increased mortality when using a liberal transfusion policy, 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.

Erythropoiesis-Stimulating Agents
Erythropoiesis-stimulating agents (ESAs) approved in the United States include epoetin-alfa (Procrit, Epogen) and darbepoetin-alfa (Aranesp). The primary indications are for anemia due to chronic kidney disease or cancer chemotherapy. 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),[89] the risks and benefits associated with the treatment in patients with chronic kidney disease, particularly older adults not on dialysis and not receiving RBC transfusions, remain unexplored. In light of the increased risk of thrombosis, hypertension, and, potentially, progression of certain cancers associated with ESA use in a population at increased danger for such events,

caution must be exercised. 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, assuming all other etiologies have been excluded. 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, if the patient or caregiver understands the risks, and if a clear quality-of-life improvement can be measured. 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.[90, 91] Iron supplementation is frequently needed to prevent iron-restricted erythropoiesis once an elderly patient is on ESA treatment.

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